diff --git a/hibernate-core/src/main/java/org/hibernate/dialect/SybaseASESqlAstTranslator.java b/hibernate-core/src/main/java/org/hibernate/dialect/SybaseASESqlAstTranslator.java
index de0370224946..f1d85e6c31d2 100644
--- a/hibernate-core/src/main/java/org/hibernate/dialect/SybaseASESqlAstTranslator.java
+++ b/hibernate-core/src/main/java/org/hibernate/dialect/SybaseASESqlAstTranslator.java
@@ -359,28 +359,11 @@ protected void renderOffsetExpression(Expression offsetExpression) {
 	protected void renderComparison(Expression lhs, ComparisonOperator operator, Expression rhs) {
 		// In Sybase ASE, XMLTYPE is not "comparable", so we have to cast the two parts to varchar for this purpose
 		final boolean isLob = isLob( lhs.getExpressionType() );
+		final boolean ansiNullOn = ((SybaseASEDialect) getDialect()).isAnsiNullOn();
 		if ( isLob ) {
 			switch ( operator ) {
-				case EQUAL:
-					lhs.accept( this );
-					appendSql( " like " );
-					rhs.accept( this );
-					return;
-				case NOT_EQUAL:
-					lhs.accept( this );
-					appendSql( " not like " );
-					rhs.accept( this );
-					return;
-				default:
-					// Fall through
-					break;
-			}
-		}
-		// I think intersect is only supported in 16.0 SP3
-		if ( ( (SybaseASEDialect) getDialect() ).isAnsiNullOn() ) {
-			if ( isLob ) {
-				switch ( operator ) {
-					case DISTINCT_FROM:
+				case DISTINCT_FROM:
+					if ( ansiNullOn ) {
 						appendSql( "case when " );
 						lhs.accept( this );
 						appendSql( " like " );
@@ -390,8 +373,20 @@ protected void renderComparison(Expression lhs, ComparisonOperator operator, Exp
 						appendSql( " is null and " );
 						rhs.accept( this );
 						appendSql( " is null then 0 else 1 end=1" );
-						return;
-					case NOT_DISTINCT_FROM:
+					}
+					else {
+						lhs.accept( this );
+						appendSql( " not like " );
+						rhs.accept( this );
+						appendSql( " and (" );
+						lhs.accept( this );
+						appendSql( " is not null or " );
+						rhs.accept( this );
+						appendSql( " is not null)" );
+					}
+					return;
+				case NOT_DISTINCT_FROM:
+					if ( ansiNullOn ) {
 						appendSql( "case when " );
 						lhs.accept( this );
 						appendSql( " like " );
@@ -401,12 +396,42 @@ protected void renderComparison(Expression lhs, ComparisonOperator operator, Exp
 						appendSql( " is null and " );
 						rhs.accept( this );
 						appendSql( " is null then 0 else 1 end=0" );
-						return;
-					default:
-						// Fall through
-						break;
-				}
+					}
+					else {
+						lhs.accept( this );
+						appendSql( " like " );
+						rhs.accept( this );
+						appendSql( " or " );
+						lhs.accept( this );
+						appendSql( " is null and " );
+						rhs.accept( this );
+						appendSql( " is null" );
+					}
+					return;
+				case EQUAL:
+					lhs.accept( this );
+					appendSql( " like " );
+					rhs.accept( this );
+					return;
+				case NOT_EQUAL:
+					lhs.accept( this );
+					appendSql( " not like " );
+					rhs.accept( this );
+					if ( !ansiNullOn ) {
+						appendSql( " and " );
+						lhs.accept( this );
+						appendSql( " is not null and " );
+						rhs.accept( this );
+						appendSql( " is not null" );
+					}
+					return;
+				default:
+					// Fall through
+					break;
 			}
+		}
+		// I think intersect is only supported in 16.0 SP3
+		if ( ansiNullOn ) {
 			if ( supportsDistinctFromPredicate() ) {
 				renderComparisonEmulateIntersect( lhs, operator, rhs );
 			}
@@ -417,50 +442,28 @@ protected void renderComparison(Expression lhs, ComparisonOperator operator, Exp
 		else {
 			// The ansinull setting only matters if using a parameter or literal and the eq operator according to the docs
 			// http://infocenter.sybase.com/help/index.jsp?topic=/com.sybase.infocenter.dc32300.1570/html/sqlug/sqlug89.htm
-			boolean rhsNotNullPredicate =
-					lhs instanceof Literal
-					|| isParameter( lhs );
-			boolean lhsNotNullPredicate =
-					rhs instanceof Literal
-					|| isParameter( rhs );
-			if ( rhsNotNullPredicate || lhsNotNullPredicate ) {
+			boolean lhsAffectedByAnsiNullOff = lhs instanceof Literal || isParameter( lhs );
+			boolean rhsAffectedByAnsiNullOff = rhs instanceof Literal || isParameter( rhs );
+			if ( lhsAffectedByAnsiNullOff || rhsAffectedByAnsiNullOff ) {
 				lhs.accept( this );
 				switch ( operator ) {
 					case DISTINCT_FROM:
-						if ( isLob ) {
-							appendSql( " not like " );
-						}
-						else {
-							appendSql( "<>" );
-						}
+						// Since this is the ansinull=off case, this comparison is enough
+						appendSql( "<>" );
 						break;
 					case NOT_DISTINCT_FROM:
-						if ( isLob ) {
-							appendSql( " like " );
-						}
-						else {
-							appendSql( '=' );
-						}
+						// Since this is the ansinull=off case, this comparison is enough
+						appendSql( '=' );
 						break;
-					case LESS_THAN:
-					case GREATER_THAN:
-					case LESS_THAN_OR_EQUAL:
-					case GREATER_THAN_OR_EQUAL:
-						// These operators are not affected by ansinull=off
-						lhsNotNullPredicate = false;
-						rhsNotNullPredicate = false;
 					default:
 						appendSql( operator.sqlText() );
 						break;
 				}
 				rhs.accept( this );
-				if ( lhsNotNullPredicate ) {
+				if ( operator == ComparisonOperator.EQUAL || operator == ComparisonOperator.NOT_EQUAL ) {
 					appendSql( " and " );
 					lhs.accept( this );
-					appendSql( " is not null" );
-				}
-				if ( rhsNotNullPredicate ) {
-					appendSql( " and " );
+					appendSql( " is not null and " );
 					rhs.accept( this );
 					appendSql( " is not null" );
 				}
diff --git a/hibernate-core/src/test/java/org/hibernate/orm/test/dialect/AnsiNullTest.java b/hibernate-core/src/test/java/org/hibernate/orm/test/dialect/AnsiNullTest.java
new file mode 100644
index 000000000000..759e18c48fd6
--- /dev/null
+++ b/hibernate-core/src/test/java/org/hibernate/orm/test/dialect/AnsiNullTest.java
@@ -0,0 +1,256 @@
+/*
+ * SPDX-License-Identifier: LGPL-2.1-or-later
+ * Copyright Red Hat Inc. and Hibernate Authors
+ */
+package org.hibernate.orm.test.dialect;
+
+import jakarta.persistence.Entity;
+import jakarta.persistence.Id;
+import org.hibernate.dialect.SybaseASEDialect;
+import org.hibernate.engine.jdbc.connections.internal.DriverManagerConnectionProviderImpl;
+import org.hibernate.orm.test.length.WithLongStrings;
+import org.hibernate.testing.orm.junit.DomainModel;
+import org.hibernate.testing.orm.junit.Jira;
+import org.hibernate.testing.orm.junit.RequiresDialect;
+import org.hibernate.testing.orm.junit.ServiceRegistry;
+import org.hibernate.testing.orm.junit.SessionFactory;
+import org.hibernate.testing.orm.junit.SessionFactoryScope;
+import org.hibernate.testing.orm.junit.Setting;
+import org.junit.jupiter.api.AfterEach;
+import org.junit.jupiter.api.Assertions;
+import org.junit.jupiter.api.BeforeEach;
+import org.junit.jupiter.api.Test;
+
+import java.util.List;
+
+/**
+ * @author Jan Schatteman
+ */
+@Jira( value = "https://hibernate.atlassian.net/browse/HHH-16216" )
+public class AnsiNullTest {
+
+	private int lob1;
+	private int lob2;
+
+	@BeforeEach
+	void setUp(SessionFactoryScope scope) {
+		scope.inTransaction( session -> {
+					session.persist( new Book( 1L, "LoremIpsum" ) );
+					session.persist( new Book( 2L, null ) );
+				}
+		);
+		lob1 = scope.fromTransaction( session -> {
+					WithLongStrings wls = new WithLongStrings();
+					wls.longish = "Short String";
+					wls.long32 = "Some long String".repeat( 100 );
+					session.persist( wls );
+					return wls.id;
+				}
+		);
+		lob2 = scope.fromTransaction( session -> {
+					WithLongStrings wls = new WithLongStrings();
+					wls.longish = "Short String";
+					session.persist( wls );
+					return wls.id;
+				}
+		);
+	}
+
+	@AfterEach
+	void tearDown(SessionFactoryScope scope) {
+		scope.inTransaction(
+				session -> {
+					session.createMutationQuery( "delete from Book" ).executeUpdate();
+					session.createMutationQuery( "delete from WithLongStrings" ).executeUpdate();
+				}
+		);
+	}
+
+	@Test
+	@RequiresDialect(value = SybaseASEDialect.class)
+	@DomainModel(annotatedClasses = { AnsiNullTest.Book.class, WithLongStrings.class })
+	@SessionFactory
+	@ServiceRegistry( settings = {@Setting(name = DriverManagerConnectionProviderImpl.INIT_SQL, value = "set ansinull on")} )
+	public void testWithAnsiNullOn(SessionFactoryScope scope) {
+		scope.inTransaction(
+				session -> {
+					Book b = session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 1L, b.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null OR b.id > 1", Book.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null OR b.id >= 1", Book.class ).list().size() );
+
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null OR b.id < 2", Book.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null OR b.id <= 2", Book.class ).list().size() );
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title = null", Book.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title = null AND b.id <= 2", Book.class ).list().size());
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title = null OR b.id > 1", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null", Book.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null AND b.id < 2", Book.class ).list().size());
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title != null OR b.id < 2", Book.class ).getSingleResult();
+					Assertions.assertEquals( 1L, b.id);
+
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title != null or id = 2", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+					b = session.createQuery( "SELECT b FROM Book b WHERE id = 2 or b.title != null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE id = 1 and b.title != null", Book.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null and id = 1", Book.class ).list().size() );
+
+					List<Book> books = session.createQuery( "SELECT b FROM Book b WHERE 1 = 1", Book.class ).list();
+					Assertions.assertEquals( 2, books.size());
+				}
+		);
+	}
+
+	@Test
+	@RequiresDialect(value = SybaseASEDialect.class)
+	@DomainModel(annotatedClasses = { AnsiNullTest.Book.class, WithLongStrings.class })
+	@SessionFactory
+	@ServiceRegistry( settings = {@Setting(name = DriverManagerConnectionProviderImpl.INIT_SQL, value = "set ansinull on")} )
+	public void testLOBWithAnsiNullOn(SessionFactoryScope scope) {
+		scope.inTransaction(
+				session -> {
+					WithLongStrings w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob1, w.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null OR w.id > 1", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null OR w.id >= 1", WithLongStrings.class ).list().size() );
+
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null OR w.id < 2", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null OR w.id <= 2", WithLongStrings.class ).list().size() );
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null", WithLongStrings.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null AND w.id <= " + lob2, WithLongStrings.class ).list().size());
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null OR w.id > 1", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null", WithLongStrings.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null AND w.id < " + lob2, WithLongStrings.class ).list().size());
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null OR w.id > 1", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null or id = " + lob2, WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( 2L, w.id);
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE id = " + lob2 + " or w.long32 != null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( 2L, w.id);
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE id = " + lob1 + " and w.long32 != null", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null and id = " + lob1, WithLongStrings.class ).list().size() );
+
+					List<WithLongStrings> ws = session.createQuery( "SELECT w FROM WithLongStrings w WHERE 1 = 1", WithLongStrings.class ).list();
+					Assertions.assertEquals( 2, ws.size());
+				}
+		);
+	}
+
+	@Test
+	@RequiresDialect(value = SybaseASEDialect.class)
+	@DomainModel(annotatedClasses = { AnsiNullTest.Book.class, WithLongStrings.class })
+	@SessionFactory
+	@ServiceRegistry( settings = {@Setting(name = DriverManagerConnectionProviderImpl.INIT_SQL, value = "set ansinull off")} )
+	public void testWithAnsiNullOff(SessionFactoryScope scope) {
+		scope.inTransaction(
+				session -> {
+					Book b = session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 1L, b.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null OR b.id > 1", Book.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS DISTINCT FROM null OR b.id >= 1", Book.class ).list().size() );
+
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null OR b.id < 2", Book.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT b FROM Book b WHERE b.title IS NOT DISTINCT FROM null OR b.id <= 2", Book.class ).list().size() );
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title = null", Book.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title = null AND b.id <= 2", Book.class ).list().size());
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title = null OR b.id > 1", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null", Book.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null AND b.id < 2", Book.class ).list().size());
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title != null OR b.id < 2", Book.class ).getSingleResult();
+					Assertions.assertEquals( 1L, b.id);
+
+					b = session.createQuery( "SELECT b FROM Book b WHERE b.title != null or id = 2", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+					b = session.createQuery( "SELECT b FROM Book b WHERE id = 2 or b.title != null", Book.class ).getSingleResult();
+					Assertions.assertEquals( 2L, b.id);
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE id = 1 and b.title != null", Book.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT b FROM Book b WHERE b.title != null and id = 1", Book.class ).list().size() );
+
+					List<Book> books = session.createQuery( "SELECT b FROM Book b WHERE 1 = 1", Book.class ).list();
+					Assertions.assertEquals( 2, books.size());
+				}
+		);
+	}
+
+	@Test
+	@RequiresDialect(value = SybaseASEDialect.class)
+	@DomainModel(annotatedClasses = { AnsiNullTest.Book.class, WithLongStrings.class })
+	@SessionFactory
+	@ServiceRegistry( settings = {@Setting(name = DriverManagerConnectionProviderImpl.INIT_SQL, value = "set ansinull off")} )
+	public void testLOBWithAnsiNullOff(SessionFactoryScope scope) {
+		scope.inTransaction(
+				session -> {
+					WithLongStrings w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob1, w.id);
+
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null OR w.id > 1", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS DISTINCT FROM null OR w.id >= 1", WithLongStrings.class ).list().size() );
+
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null OR w.id < 2", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 2, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 IS NOT DISTINCT FROM null OR w.id <= 2", WithLongStrings.class ).list().size() );
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null", WithLongStrings.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null AND w.id <= " + lob2, WithLongStrings.class ).list().size());
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 = null OR w.id > 1", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null", WithLongStrings.class ).list().size());
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null AND w.id < " + lob2, WithLongStrings.class ).list().size());
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null OR w.id > 1", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( lob2, w.id);
+
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null or id = " + lob2, WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( 2L, w.id);
+					w = session.createQuery( "SELECT w FROM WithLongStrings w WHERE id = " + lob2 + " or w.long32 != null", WithLongStrings.class ).getSingleResult();
+					Assertions.assertEquals( 2L, w.id);
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE id = " + lob1 + " and w.long32 != null", WithLongStrings.class ).list().size() );
+					Assertions.assertEquals( 0, session.createQuery( "SELECT w FROM WithLongStrings w WHERE w.long32 != null and id = " + lob1, WithLongStrings.class ).list().size() );
+
+					List<WithLongStrings> ws = session.createQuery( "SELECT w FROM WithLongStrings w WHERE 1 = 1", WithLongStrings.class ).list();
+					Assertions.assertEquals( 2, ws.size());
+				}
+		);
+	}
+
+	@Entity(name = "Book")
+	static class Book {
+		@Id
+		Long id;
+		String title;
+
+		public Book() {
+		}
+
+		public Book(Long id, String title) {
+			this.id = id;
+			this.title = title;
+		}
+	}
+
+}