diff --git a/doc/source/whatsnew/v1.2.0.rst b/doc/source/whatsnew/v1.2.0.rst
index 48561b50f66ae..ad5af5df710ba 100644
--- a/doc/source/whatsnew/v1.2.0.rst
+++ b/doc/source/whatsnew/v1.2.0.rst
@@ -621,6 +621,7 @@ Indexing
 - Bug in :meth:`DataFrame.iloc` and :meth:`Series.iloc` aligning objects in ``__setitem__`` (:issue:`22046`)
 - Bug in :meth:`DataFrame.loc` did not raise ``KeyError`` when missing combination was given with ``slice(None)`` for remaining levels (:issue:`19556`)
 - Bug in :meth:`DataFrame.loc` raising ``TypeError`` when non-integer slice was given to select values from :class:`MultiIndex` (:issue:`25165`, :issue:`24263`)
+- Bug in :meth:`DataFrame.loc` and :meth:`DataFrame.__getitem__`  raising ``KeyError`` when columns were :class:`MultiIndex` with only one level (:issue:`29749`)
 
 Missing
 ^^^^^^^
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 6f6d94f0e9f8e..5b87c4ea8b9cc 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -2935,7 +2935,7 @@ def __getitem__(self, key):
         if is_hashable(key):
             # shortcut if the key is in columns
             if self.columns.is_unique and key in self.columns:
-                if self.columns.nlevels > 1:
+                if isinstance(self.columns, MultiIndex):
                     return self._getitem_multilevel(key)
                 return self._get_item_cache(key)
 
diff --git a/pandas/tests/frame/indexing/test_getitem.py b/pandas/tests/frame/indexing/test_getitem.py
index 868df82a43a91..6c6b4e002644c 100644
--- a/pandas/tests/frame/indexing/test_getitem.py
+++ b/pandas/tests/frame/indexing/test_getitem.py
@@ -96,6 +96,17 @@ def test_getitem_callable(self, float_frame):
         expected = float_frame.iloc[[0, 2], :]
         tm.assert_frame_equal(result, expected)
 
+    def test_loc_multiindex_columns_one_level(self):
+        # GH#29749
+        df = DataFrame([[1, 2]], columns=[["a", "b"]])
+        expected = DataFrame([1], columns=[["a"]])
+
+        result = df["a"]
+        tm.assert_frame_equal(result, expected)
+
+        result = df.loc[:, "a"]
+        tm.assert_frame_equal(result, expected)
+
 
 class TestGetitemBooleanMask:
     def test_getitem_bool_mask_categorical_index(self):