diff --git a/Lib/ctypes/test/test_struct_fields.py b/Lib/ctypes/test/test_struct_fields.py
index ee8415f3e63..fefeaea1496 100644
--- a/Lib/ctypes/test/test_struct_fields.py
+++ b/Lib/ctypes/test/test_struct_fields.py
@@ -54,6 +54,15 @@ class X(Structure):
         x.char = b'a\0b\0'
         self.assertEqual(bytes(x), b'a\x00###')
 
+    def test_gh99275(self):
+        class BrokenStructure(Structure):
+            def __init_subclass__(cls, **kwargs):
+                cls._fields_ = []  # This line will fail, `stgdict` is not ready
+
+        with self.assertRaisesRegex(TypeError,
+                                    'ctypes state is not initialized'):
+            class Subclass(BrokenStructure): ...
+
     # __set__ and __get__ should raise a TypeError in case their self
     # argument is not a ctype instance.
     def test___set__(self):
diff --git a/Misc/NEWS.d/next/Library/2022-11-09-12-16-35.gh-issue-99275.klOqoL.rst b/Misc/NEWS.d/next/Library/2022-11-09-12-16-35.gh-issue-99275.klOqoL.rst
new file mode 100644
index 00000000000..2bf05a3bdfb
--- /dev/null
+++ b/Misc/NEWS.d/next/Library/2022-11-09-12-16-35.gh-issue-99275.klOqoL.rst
@@ -0,0 +1,2 @@
+Fix ``SystemError`` in :mod:`ctypes` when exception was not set during
+``__initsubclass__``.
diff --git a/Modules/_ctypes/stgdict.c b/Modules/_ctypes/stgdict.c
index a819ce910d4..88999b8dff1 100644
--- a/Modules/_ctypes/stgdict.c
+++ b/Modules/_ctypes/stgdict.c
@@ -430,8 +430,11 @@ PyCStructUnionType_update_stgdict(PyObject *type, PyObject *fields, int isStruct
     }
 
     stgdict = PyType_stgdict(type);
-    if (!stgdict)
+    if (!stgdict) {
+        PyErr_SetString(PyExc_TypeError,
+                        "ctypes state is not initialized");
         return -1;
+    }
     /* If this structure/union is already marked final we cannot assign
        _fields_ anymore. */