diff --git a/testtools/matchers/_basic.py b/testtools/matchers/_basic.py
index b3451a53..2f40e259 100644
--- a/testtools/matchers/_basic.py
+++ b/testtools/matchers/_basic.py
@@ -73,6 +73,14 @@ def __init__(self, actual, mismatch_string, reference, reference_on_right=True):
         self._reference_on_right = reference_on_right
 
     def describe(self):
+        # Special handling for set comparisons
+        if (
+            self._mismatch_string == "!="
+            and isinstance(self._reference, set)
+            and isinstance(self._actual, set)
+        ):
+            return self._describe_set_difference()
+
         actual = repr(self._actual)
         reference = repr(self._reference)
         if len(actual) + len(reference) > 70:
@@ -88,6 +96,27 @@ def describe(self):
                 left, right = reference, actual
             return f"{left} {self._mismatch_string} {right}"
 
+    def _describe_set_difference(self):
+        """Describe the difference between two sets in a readable format."""
+        reference_only = sorted(
+            self._reference - self._actual, key=lambda x: (type(x).__name__, x)
+        )
+        actual_only = sorted(
+            self._actual - self._reference, key=lambda x: (type(x).__name__, x)
+        )
+
+        lines = ["!=:"]
+        if reference_only:
+            lines.append(
+                f"Items in expected but not in actual:\n{_format(reference_only)}"
+            )
+        if actual_only:
+            lines.append(
+                f"Items in actual but not in expected:\n{_format(actual_only)}"
+            )
+
+        return "\n".join(lines)
+
 
 class Equals(_BinaryComparison):
     """Matches if the items are equal."""
diff --git a/testtools/tests/test_testcase.py b/testtools/tests/test_testcase.py
index c4764310..c304af6a 100644
--- a/testtools/tests/test_testcase.py
+++ b/testtools/tests/test_testcase.py
@@ -863,6 +863,44 @@ def test_assertEqual_non_ascii_str_with_newlines(self):
         )
         self.assertFails(expected_error, self.assertEqual, a, b, message)
 
+    def test_assertEqual_set_difference(self):
+        a = {1, 2, 3, 4}
+        b = {2, 3, 5, 6}
+        expected_error = "\n".join(
+            [
+                "!=:",
+                "Items in expected but not in actual:",
+                "[1, 4]",
+                "Items in actual but not in expected:",
+                "[5, 6]",
+            ]
+        )
+        self.assertFails(expected_error, self.assertEqual, a, b)
+
+    def test_assertEqual_set_missing_items_only(self):
+        a = {1, 2, 3, 4}
+        b = {2, 3}
+        expected_error = "\n".join(
+            [
+                "!=:",
+                "Items in expected but not in actual:",
+                "[1, 4]",
+            ]
+        )
+        self.assertFails(expected_error, self.assertEqual, a, b)
+
+    def test_assertEqual_set_extra_items_only(self):
+        a = {1, 2}
+        b = {1, 2, 3, 4}
+        expected_error = "\n".join(
+            [
+                "!=:",
+                "Items in actual but not in expected:",
+                "[3, 4]",
+            ]
+        )
+        self.assertFails(expected_error, self.assertEqual, a, b)
+
     def test_assertIsNone(self):
         self.assertIsNone(None)