diff --git a/Lib/test/test_typing.py b/Lib/test/test_typing.py
index dfbe2d9d34c8ff..3894ab43b5d657 100644
--- a/Lib/test/test_typing.py
+++ b/Lib/test/test_typing.py
@@ -51,6 +51,10 @@
 c_typing = import_helper.import_fresh_module('typing', fresh=['_typing'])
 
 
+CANNOT_SUBCLASS_TYPE = 'Cannot subclass special typing classes'
+CANNOT_SUBCLASS_INSTANCE = 'Cannot subclass an instance of %s'
+
+
 class BaseTestCase(TestCase):
 
     def assertIsSubclass(self, cls, class_or_tuple, msg=None):
@@ -170,10 +174,11 @@ def test_not_generic(self):
             self.bottom_type[int]
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                'Cannot subclass ' + re.escape(str(self.bottom_type))):
             class A(self.bottom_type):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class A(type(self.bottom_type)):
                 pass
 
@@ -266,10 +271,11 @@ def test_cannot_subscript(self):
             Self[int]
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Self)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.Self'):
             class C(Self):
                 pass
 
@@ -322,10 +328,11 @@ def test_cannot_subscript(self):
             LiteralString[int]
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(LiteralString)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.LiteralString'):
             class C(LiteralString):
                 pass
 
@@ -415,15 +422,13 @@ def test_no_redefinition(self):
         self.assertNotEqual(TypeVar('T'), TypeVar('T'))
         self.assertNotEqual(TypeVar('T', int, str), TypeVar('T', int, str))
 
-    def test_cannot_subclass_vars(self):
-        with self.assertRaises(TypeError):
-            class V(TypeVar('T')):
-                pass
-
-    def test_cannot_subclass_var_itself(self):
-        with self.assertRaises(TypeError):
-            class V(TypeVar):
-                pass
+    def test_cannot_subclass(self):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
+            class V(TypeVar): pass
+        T = TypeVar("T")
+        with self.assertRaisesRegex(TypeError,
+                CANNOT_SUBCLASS_INSTANCE % 'TypeVar'):
+            class V(T): pass
 
     def test_cannot_instantiate_vars(self):
         with self.assertRaises(TypeError):
@@ -1016,15 +1021,14 @@ class A(Generic[Unpack[Ts]]): pass
         self.assertEndsWith(repr(F[float]), 'A[float, *tuple[str, ...]]')
         self.assertEndsWith(repr(F[float, str]), 'A[float, str, *tuple[str, ...]]')
 
-    def test_cannot_subclass_class(self):
-        with self.assertRaises(TypeError):
+    def test_cannot_subclass(self):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(TypeVarTuple): pass
-
-    def test_cannot_subclass_instance(self):
         Ts = TypeVarTuple('Ts')
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                CANNOT_SUBCLASS_INSTANCE % 'TypeVarTuple'):
             class C(Ts): pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, r'Cannot subclass \*Ts'):
             class C(Unpack[Ts]): pass
 
     def test_variadic_class_args_are_correct(self):
@@ -1411,13 +1415,15 @@ def test_repr(self):
         self.assertEqual(repr(u), 'typing.Optional[str]')
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.Union'):
             class C(Union):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Union)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.Union\[int, str\]'):
             class C(Union[int, str]):
                 pass
 
@@ -3658,10 +3664,10 @@ def test_repr(self):
         self.assertEqual(repr(cv), 'typing.ClassVar[%s.Employee]' % __name__)
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(ClassVar)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(ClassVar[int])):
                 pass
 
@@ -3700,10 +3706,10 @@ def test_repr(self):
         self.assertEqual(repr(cv), 'typing.Final[tuple[int]]')
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Final)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Final[int])):
                 pass
 
@@ -6206,16 +6212,18 @@ def test_repr(self):
         self.assertEqual(repr(cv), f'typing.Required[{__name__}.Employee]')
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Required)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(Required[int])):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.Required'):
             class C(Required):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.Required\[int\]'):
             class C(Required[int]):
                 pass
 
@@ -6252,16 +6260,18 @@ def test_repr(self):
         self.assertEqual(repr(cv), f'typing.NotRequired[{__name__}.Employee]')
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(NotRequired)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(NotRequired[int])):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.NotRequired'):
             class C(NotRequired):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.NotRequired\[int\]'):
             class C(NotRequired[int]):
                 pass
 
@@ -6677,7 +6687,8 @@ def test_no_issubclass(self):
             issubclass(TypeAlias, Employee)
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError,
+                r'Cannot subclass typing\.TypeAlias'):
             class C(TypeAlias):
                 pass
 
@@ -6879,6 +6890,24 @@ def test_paramspec_gets_copied(self):
         self.assertEqual(C2[Concatenate[str, P2]].__parameters__, (P2,))
         self.assertEqual(C2[Concatenate[T, P2]].__parameters__, (T, P2))
 
+    def test_cannot_subclass(self):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
+            class C(ParamSpec): pass
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
+            class C(ParamSpecArgs): pass
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
+            class C(ParamSpecKwargs): pass
+        P = ParamSpec('P')
+        with self.assertRaisesRegex(TypeError,
+                CANNOT_SUBCLASS_INSTANCE % 'ParamSpec'):
+            class C(P): pass
+        with self.assertRaisesRegex(TypeError,
+                CANNOT_SUBCLASS_INSTANCE % 'ParamSpecArgs'):
+            class C(P.args): pass
+        with self.assertRaisesRegex(TypeError,
+                CANNOT_SUBCLASS_INSTANCE % 'ParamSpecKwargs'):
+            class C(P.kwargs): pass
+
 
 class ConcatenateTests(BaseTestCase):
     def test_basics(self):
@@ -6945,10 +6974,10 @@ def test_repr(self):
         self.assertEqual(repr(cv), 'typing.TypeGuard[tuple[int]]')
 
     def test_cannot_subclass(self):
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(TypeGuard)):
                 pass
-        with self.assertRaises(TypeError):
+        with self.assertRaisesRegex(TypeError, CANNOT_SUBCLASS_TYPE):
             class C(type(TypeGuard[int])):
                 pass
 
diff --git a/Lib/typing.py b/Lib/typing.py
index 1ebc3ce1f64bd6..25ae19f71fe94a 100644
--- a/Lib/typing.py
+++ b/Lib/typing.py
@@ -954,6 +954,9 @@ def __repr__(self):
             prefix = '~'
         return prefix + self.__name__
 
+    def __mro_entries__(self, bases):
+        raise TypeError(f"Cannot subclass an instance of {type(self).__name__}")
+
 
 class TypeVar(_Final, _Immutable, _BoundVarianceMixin, _PickleUsingNameMixin,
               _root=True):
@@ -1101,6 +1104,9 @@ def __typing_prepare_subst__(self, alias, args):
             *args[alen - right:],
         )
 
+    def __mro_entries__(self, bases):
+        raise TypeError(f"Cannot subclass an instance of {type(self).__name__}")
+
 
 class ParamSpecArgs(_Final, _Immutable, _root=True):
     """The args for a ParamSpec object.
@@ -1125,6 +1131,9 @@ def __eq__(self, other):
             return NotImplemented
         return self.__origin__ == other.__origin__
 
+    def __mro_entries__(self, bases):
+        raise TypeError(f"Cannot subclass an instance of {type(self).__name__}")
+
 
 class ParamSpecKwargs(_Final, _Immutable, _root=True):
     """The kwargs for a ParamSpec object.
@@ -1149,6 +1158,9 @@ def __eq__(self, other):
             return NotImplemented
         return self.__origin__ == other.__origin__
 
+    def __mro_entries__(self, bases):
+        raise TypeError(f"Cannot subclass an instance of {type(self).__name__}")
+
 
 class ParamSpec(_Final, _Immutable, _BoundVarianceMixin, _PickleUsingNameMixin,
                 _root=True):
diff --git a/Misc/NEWS.d/next/Library/2022-02-05-18-46-54.bpo-46642.YI6nHQ.rst b/Misc/NEWS.d/next/Library/2022-02-05-18-46-54.bpo-46642.YI6nHQ.rst
new file mode 100644
index 00000000000000..2d2815c1e4b00d
--- /dev/null
+++ b/Misc/NEWS.d/next/Library/2022-02-05-18-46-54.bpo-46642.YI6nHQ.rst
@@ -0,0 +1 @@
+Improve error message when trying to subclass an instance of :data:`typing.TypeVar`, :data:`typing.ParamSpec`, :data:`typing.TypeVarTuple`, etc. Based on patch by Gregory Beauregard.