diff -r 824ba744b999 Lib/inspect.py
--- a/Lib/inspect.py	Tue Jan 28 23:32:40 2014 +0100
+++ b/Lib/inspect.py	Tue Jan 28 17:57:08 2014 -0500
@@ -1486,7 +1486,14 @@
                         not param._partial_kwarg):
             new_params.pop(arg_name)
 
-    return wrapped_sig.replace(parameters=new_params.values())
+    # We don't use '.replace' method here, as signatures for partial
+    # objects may bot be valid python signatures, i.e. parameters with
+    # defaults can be before parameters without defaults, etc. Therefore,
+    # we construct the Signature object manually, passing
+    # '__validate_parameters__ = False'.
+    return type(wrapped_sig)(parameters=new_params.values(),
+                             return_annotation=wrapped_sig.return_annotation,
+                             __validate_parameters__=False)
 
 
 def _signature_bound_method(sig):
@@ -1918,6 +1925,7 @@
             if __validate_parameters__:
                 params = OrderedDict()
                 top_kind = _POSITIONAL_ONLY
+                kind_defaults = False
 
                 for idx, param in enumerate(parameters):
                     kind = param.kind
@@ -1927,9 +1935,19 @@
                         msg = 'wrong parameter order: {} before {}'
                         msg = msg.format(top_kind, kind)
                         raise ValueError(msg)
-                    else:
+                    elif kind > top_kind:
+                        kind_defaults = False
                         top_kind = kind
 
+                    if kind in (_POSITIONAL_ONLY, _POSITIONAL_OR_KEYWORD):
+                        if param.default is _empty:
+                            if kind_defaults:
+                                msg = 'non-default argument follows default ' \
+                                      'argument'
+                                raise ValueError(msg)
+                        else:
+                            kind_defaults = True
+
                     if name in params:
                         msg = 'duplicate parameter name: {!r}'.format(name)
                         raise ValueError(msg)
diff -r 824ba744b999 Lib/test/test_inspect.py
--- a/Lib/test/test_inspect.py	Tue Jan 28 23:32:40 2014 +0100
+++ b/Lib/test/test_inspect.py	Tue Jan 28 17:57:08 2014 -0500
@@ -1522,11 +1522,13 @@
 
         self.assertEqual(str(S()), '()')
 
-        def test(po, pk, *args, ko, **kwargs):
+        def test(po, pk, pod=42, pkd=100, *args, ko, **kwargs):
             pass
         sig = inspect.signature(test)
         po = sig.parameters['po'].replace(kind=P.POSITIONAL_ONLY)
+        pod = sig.parameters['pod'].replace(kind=P.POSITIONAL_ONLY)
         pk = sig.parameters['pk']
+        pkd = sig.parameters['pkd']
         args = sig.parameters['args']
         ko = sig.parameters['ko']
         kwargs = sig.parameters['kwargs']
@@ -1549,6 +1551,12 @@
         with self.assertRaisesRegex(ValueError, 'duplicate parameter name'):
             S((po, pk, args, kwargs2, ko))
 
+        with self.assertRaisesRegex(ValueError, 'follows default argument'):
+            S((pod, po))
+
+        with self.assertRaisesRegex(ValueError, 'follows default argument'):
+            S((po, pkd, pk))
+
     def test_signature_immutability(self):
         def test(a):
             pass