diff --git a/mypyc/ir/class_ir.py b/mypyc/ir/class_ir.py
index 0a56aaf5d101..d3771511b98e 100644
--- a/mypyc/ir/class_ir.py
+++ b/mypyc/ir/class_ir.py
@@ -333,7 +333,11 @@ def has_method_decl(self, name: str) -> bool:
         return any(name in ir.method_decls for ir in self.mro)
 
     def has_no_subclasses(self) -> bool:
-        return self.children == [] and not self.allow_interpreted_subclasses
+        return (
+            self.children == []
+            and not self.allow_interpreted_subclasses
+            and (self.is_ext_class or self.is_final_class)
+        )
 
     def subclasses(self) -> set[ClassIR] | None:
         """Return all subclasses of this class, both direct and indirect.
@@ -341,15 +345,18 @@ def subclasses(self) -> set[ClassIR] | None:
         Return None if it is impossible to identify all subclasses, for example
         because we are performing separate compilation.
         """
-        if self.children is None or self.allow_interpreted_subclasses:
+        if (
+            (not self.is_ext_class and not self.is_final_class)
+            or self.allow_interpreted_subclasses
+            or self.children is None
+        ):
             return None
         result = set(self.children)
         for child in self.children:
-            if child.children:
-                child_subs = child.subclasses()
-                if child_subs is None:
-                    return None
-                result.update(child_subs)
+            child_subs = child.subclasses()
+            if child_subs is None:
+                return None
+            result.update(child_subs)
         return result
 
     def concrete_subclasses(self) -> list[ClassIR] | None:
diff --git a/mypyc/irbuild/ll_builder.py b/mypyc/irbuild/ll_builder.py
index fd66288dbcc5..026f3780c88e 100644
--- a/mypyc/irbuild/ll_builder.py
+++ b/mypyc/irbuild/ll_builder.py
@@ -697,8 +697,8 @@ def isinstance_native(self, obj: Value, class_ir: ClassIR, line: int) -> Value:
         """Fast isinstance() check for a native class.
 
         If there are three or fewer concrete (non-trait) classes among the class
-        and all its children, use even faster type comparison checks `type(obj)
-        is typ`.
+        and all its children, and none of them allow interpreted subclasses, use
+        even faster type comparison checks `type(obj) is typ`.
         """
         concrete = all_concrete_classes(class_ir)
         if concrete is None or len(concrete) > FAST_ISINSTANCE_MAX_SUBCLASSES + 1:
diff --git a/mypyc/test-data/irbuild-classes.test b/mypyc/test-data/irbuild-classes.test
index 0f8ec2b094f0..e04bcb808d76 100644
--- a/mypyc/test-data/irbuild-classes.test
+++ b/mypyc/test-data/irbuild-classes.test
@@ -2865,3 +2865,40 @@ class InvalidKwarg:
 @mypyc_attr(str())  # E: All "mypyc_attr" positional arguments must be string literals.
 class InvalidLiteral:
     pass
+
+[case testIsInstanceInterpretedSubclasses]
+from typing import Any
+from mypy_extensions import mypyc_attr
+
+@mypyc_attr(native_class=False)
+class NonNative:
+    pass
+
+@mypyc_attr(allow_interpreted_subclasses=True)
+class InterpSubclasses:
+    pass
+
+def isinstance_nonnative(x: Any) -> bool:
+    return isinstance(x, NonNative)
+def isinstance_interpreted_subclasses(x: Any) -> bool:
+    return isinstance(x, InterpSubclasses)
+[out]
+def isinstance_nonnative(x):
+    x, r0 :: object
+    r1 :: ptr
+    r2 :: object
+    r3 :: bit
+L0:
+    r0 = __main__.NonNative :: type
+    r1 = get_element_ptr x ob_type :: PyObject
+    r2 = borrow load_mem r1 :: builtins.object*
+    keep_alive x
+    r3 = r2 == r0
+    return r3
+def isinstance_interpreted_subclasses(x):
+    x, r0 :: object
+    r1 :: bool
+L0:
+    r0 = __main__.InterpSubclasses :: type
+    r1 = CPy_TypeCheck(x, r0)
+    return r1