diff --git a/doc/source/release.rst b/doc/source/release.rst
index b74b23029a2ac..d4764dbe81a9a 100644
--- a/doc/source/release.rst
+++ b/doc/source/release.rst
@@ -642,6 +642,7 @@ Bug Fixes
     related (:issue:`5312`)
   - Fix return value/type signature of ``initObjToJSON()`` to be compatible
     with numpy's ``import_array()`` (:issue:`5334`, :issue:`5326`)
+  - Bug when renaming then set_index on a DataFrame (:issue:`5344`)
 
 pandas 0.12.0
 -------------
diff --git a/pandas/core/internals.py b/pandas/core/internals.py
index c327458e00a07..62aa95d270924 100644
--- a/pandas/core/internals.py
+++ b/pandas/core/internals.py
@@ -1992,6 +1992,9 @@ def _set_ref_locs(self, labels=None, do_refs=False):
             self._ref_locs = rl
             return rl
 
+        elif do_refs:
+            self._reset_ref_locs()
+
         # return our cached _ref_locs (or will compute again
         # when we recreate the block manager if needed
         return getattr(self, '_ref_locs', None)
diff --git a/pandas/tests/test_frame.py b/pandas/tests/test_frame.py
index 6aa4322234d7f..704493308f960 100644
--- a/pandas/tests/test_frame.py
+++ b/pandas/tests/test_frame.py
@@ -8551,6 +8551,19 @@ def test_rename_inplace(self):
         self.assert_('foo' in frame)
         self.assert_(id(frame['foo']) != c_id)
 
+    def test_rename_bug(self):
+        # GH 5344
+        # rename set ref_locs, and set_index was not resetting
+        df = DataFrame({ 0 : ['foo','bar'], 1 : ['bah','bas'], 2 : [1,2]})
+        df = df.rename(columns={0 : 'a'})
+        df = df.rename(columns={1 : 'b'})
+        df = df.set_index(['a','b'])
+        df.columns = ['2001-01-01']
+        expected = DataFrame([[1],[2]],index=MultiIndex.from_tuples([('foo','bah'),('bar','bas')],
+                                                                    names=['a','b']),
+                             columns=['2001-01-01'])
+        assert_frame_equal(df,expected)
+
     #----------------------------------------------------------------------
     # Time series related
     def test_diff(self):