diff --git a/Lib/unittest/mock.py b/Lib/unittest/mock.py
--- a/Lib/unittest/mock.py
+++ b/Lib/unittest/mock.py
@@ -2265,6 +2265,7 @@
     for line in data_as_list:
         yield line
 
+
 def mock_open(mock=None, read_data=''):
     """
     A helper function to create a mock to replace the use of `open`. It works
@@ -2277,24 +2278,6 @@
     `read_data` is a string for the `read` methoddline`, and `readlines` of the
     file handle to return.  This is an empty string by default.
     """
-    def _readlines_side_effect(*args, **kwargs):
-        if handle.readlines.return_value is not None:
-            return handle.readlines.return_value
-        return list(_data)
-
-    def _read_side_effect(*args, **kwargs):
-        if handle.read.return_value is not None:
-            return handle.read.return_value
-        return ''.join(_data)
-
-    def _readline_side_effect():
-        if handle.readline.return_value is not None:
-            while True:
-                yield handle.readline.return_value
-        for line in _data:
-            yield line
-
-
     global file_spec
     if file_spec is None:
         import _io
@@ -2303,21 +2286,42 @@
     if mock is None:
         mock = MagicMock(name='open', spec=open)
 
-    handle = MagicMock(spec=file_spec)
-    handle.__enter__.return_value = handle
-
-    _data = _iterate_read_data(read_data)
-
-    handle.write.return_value = None
-    handle.read.return_value = None
-    handle.readline.return_value = None
-    handle.readlines.return_value = None
-
-    handle.read.side_effect = _read_side_effect
-    handle.readline.side_effect = _readline_side_effect()
-    handle.readlines.side_effect = _readlines_side_effect
-
-    mock.return_value = handle
+    def make_handle(*args, **kwargs):
+        # Arg checking is handled by __call__
+        def _readlines_side_effect(*args, **kwargs):
+            if handle.readlines.return_value is not None:
+                return handle.readlines.return_value
+            return list(_data)
+
+        def _read_side_effect(*args, **kwargs):
+            if handle.read.return_value is not None:
+                return handle.read.return_value
+            return ''.join(_data)
+
+        def _readline_side_effect():
+            if handle.readline.return_value is not None:
+                while True:
+                    yield handle.readline.return_value
+            for line in _data:
+                yield line
+
+        handle = MagicMock(spec=file_spec)
+        handle.__enter__.return_value = handle
+
+        _data = _iterate_read_data(read_data)
+
+        handle.write.return_value = None
+        handle.read.return_value = None
+        handle.readline.return_value = None
+        handle.readlines.return_value = None
+
+        handle.read.side_effect = _read_side_effect
+        handle.readline.side_effect = _readline_side_effect()
+        handle.readlines.side_effect = _readlines_side_effect
+        _check_and_set_parent(mock, handle, None, '()')
+        return handle
+
+    mock.side_effect = make_handle
     return mock
 
 
diff --git a/Lib/unittest/test/testmock/testmock.py b/Lib/unittest/test/testmock/testmock.py
--- a/Lib/unittest/test/testmock/testmock.py
+++ b/Lib/unittest/test/testmock/testmock.py
@@ -1326,6 +1326,11 @@
             self.assertEqual(m.mock_calls, [call.__int__(), call.__float__()])
             self.assertEqual(m.method_calls, [])
 
+    def test_mock_open_reuse_issue_21750(self):
+        mocked_open = mock.mock_open(read_data='data')
+        f1 = mocked_open('a-name')
+        f2 = mocked_open('another-name')
+        self.assertEqual(f1.read(), f2.read())
 
     def test_mock_parents(self):
         for Klass in Mock, MagicMock:
diff --git a/Lib/unittest/test/testmock/testwith.py b/Lib/unittest/test/testmock/testwith.py
--- a/Lib/unittest/test/testmock/testwith.py
+++ b/Lib/unittest/test/testmock/testwith.py
@@ -141,7 +141,6 @@
 
     def test_mock_open_context_manager(self):
         mock = mock_open()
-        handle = mock.return_value
         with patch('%s.open' % __name__, mock, create=True):
             with open('foo') as f:
                 f.read()
@@ -149,8 +148,23 @@
         expected_calls = [call('foo'), call().__enter__(), call().read(),
                           call().__exit__(None, None, None)]
         self.assertEqual(mock.mock_calls, expected_calls)
-        self.assertIs(f, handle)
+        # mock_open.return_value is no longer static, because
+        # readline support requires that it mutate state
 
+    def test_mock_open_context_manager_multiple_times(self):
+        mock = mock_open()
+        with patch('%s.open' % __name__, mock, create=True):
+            with open('foo') as f:
+                f.read()
+            with open('bar') as f:
+                f.read()
+
+        expected_calls = [
+            call('foo'), call().__enter__(), call().read(),
+            call().__exit__(None, None, None),
+            call('bar'), call().__enter__(), call().read(),
+            call().__exit__(None, None, None)]
+        self.assertEqual(mock.mock_calls, expected_calls)
 
     def test_explicit_mock(self):
         mock = MagicMock()