diff --git a/doc/source/whatsnew/v0.23.0.txt b/doc/source/whatsnew/v0.23.0.txt
index 0301bf0a23dd5..430637ac6d384 100644
--- a/doc/source/whatsnew/v0.23.0.txt
+++ b/doc/source/whatsnew/v0.23.0.txt
@@ -314,6 +314,7 @@ Indexing
 - :func:`DatetimeIndex.to_series` now accepts ``index`` and ``name`` kwargs (:issue:`18699`)
 - Bug in indexing non-scalar value from ``Series`` having non-unique ``Index`` will return value flattened (:issue:`17610`)
 - Bug in :func:`DatetimeIndex.insert` where inserting ``NaT`` into a timezone-aware index incorrectly raised (:issue:`16357`)
+- Bug in ``__setitem__`` when indexing a :class:`DataFrame` with a 2-d boolean ndarray (:issue:`18582`)
 
 
 I/O
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 12a4a7fdaedad..faf9f2673b0ba 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -2532,10 +2532,10 @@ def __setitem__(self, key, value):
         if indexer is not None:
             return self._setitem_slice(indexer, value)
 
-        if isinstance(key, (Series, np.ndarray, list, Index)):
-            self._setitem_array(key, value)
-        elif isinstance(key, DataFrame):
+        if isinstance(key, DataFrame) or getattr(key, 'ndim', None) == 2:
             self._setitem_frame(key, value)
+        elif isinstance(key, (Series, np.ndarray, list, Index)):
+            self._setitem_array(key, value)
         else:
             # set column
             self._set_item(key, value)
@@ -2568,8 +2568,17 @@ def _setitem_array(self, key, value):
     def _setitem_frame(self, key, value):
         # support boolean setting with DataFrame input, e.g.
         # df[df > df2] = 0
+        if isinstance(key, np.ndarray):
+            if key.shape != self.shape:
+                raise ValueError(
+                    'Array conditional must be same shape as self'
+                )
+            key = self._constructor(key, **self._construct_axes_dict())
+
         if key.values.size and not is_bool_dtype(key.values):
-            raise TypeError('Must pass DataFrame with boolean values only')
+            raise TypeError(
+                'Must pass DataFrame or 2-d ndarray with boolean values only'
+            )
 
         self._check_inplace_setting(value)
         self._check_setitem_copy()
diff --git a/pandas/tests/frame/test_indexing.py b/pandas/tests/frame/test_indexing.py
index 62bc0eada9d89..882fa634d167d 100644
--- a/pandas/tests/frame/test_indexing.py
+++ b/pandas/tests/frame/test_indexing.py
@@ -524,9 +524,8 @@ def test_setitem_boolean(self):
         values[values == 2] = 3
         assert_almost_equal(df.values, values)
 
-        with tm.assert_raises_regex(TypeError, 'Must pass '
-                                    'DataFrame with '
-                                    'boolean values only'):
+        msg = "Must pass DataFrame or 2-d ndarray with boolean values only"
+        with tm.assert_raises_regex(TypeError, msg):
             df[df * 0] = 2
 
         # index with DataFrame
@@ -542,6 +541,25 @@ def test_setitem_boolean(self):
         np.putmask(expected.values, mask.values, df.values * 2)
         assert_frame_equal(df, expected)
 
+    @pytest.mark.parametrize(
+        "mask_type",
+        [lambda df: df > np.abs(df) / 2,
+         lambda df: (df > np.abs(df) / 2).values],
+        ids=['dataframe', 'array'])
+    def test_setitem_boolean_mask(self, mask_type):
+
+        # Test for issue #18582
+        df = self.frame.copy()
+        mask = mask_type(df)
+
+        # index with boolean mask
+        result = df.copy()
+        result[mask] = np.nan
+
+        expected = df.copy()
+        expected.values[np.array(mask)] = np.nan
+        assert_frame_equal(result, expected)
+
     def test_setitem_cast(self):
         self.frame['D'] = self.frame['D'].astype('i8')
         assert self.frame['D'].dtype == np.int64