diff --git a/doc/source/release.rst b/doc/source/release.rst
index 791fbc2c516b5..62ca11b6cef0b 100644
--- a/doc/source/release.rst
+++ b/doc/source/release.rst
@@ -118,6 +118,8 @@ Improvements to existing features
     thanks @lgautier
   - DataFrame constructor now accepts a numpy masked record array (:issue:`3478`),
     thanks @jnothman
+  - ``__getitem__`` with ``tuple`` key (e.g., ``[:, 2]``) on ``Series``
+    without ``MultiIndex`` raises ``ValueError`` (:issue:`4759`, :issue:`4837`)
 
 API Changes
 ~~~~~~~~~~~
diff --git a/pandas/core/series.py b/pandas/core/series.py
index 8d6591c3acd60..7d3cce8c80f72 100644
--- a/pandas/core/series.py
+++ b/pandas/core/series.py
@@ -1050,6 +1050,8 @@ def __setitem__(self, key, value):
             return
 
         except TypeError as e:
+            if isinstance(key, tuple) and not isinstance(self.index, MultiIndex):
+                raise ValueError("Can only tuple-index with a MultiIndex")
             # python 3 type errors should be raised
             if 'unorderable' in str(e):  # pragma: no cover
                 raise IndexError(key)
diff --git a/pandas/tests/test_series.py b/pandas/tests/test_series.py
index d2d0bc39fbfc9..c52fcad3d5111 100644
--- a/pandas/tests/test_series.py
+++ b/pandas/tests/test_series.py
@@ -1025,10 +1025,10 @@ def test_setslice(self):
 
     def test_basic_getitem_setitem_corner(self):
         # invalid tuples, e.g. self.ts[:, None] vs. self.ts[:, 2]
-        self.assertRaises(Exception, self.ts.__getitem__,
-                          (slice(None, None), 2))
-        self.assertRaises(Exception, self.ts.__setitem__,
-                          (slice(None, None), 2), 2)
+        with tm.assertRaisesRegexp(ValueError, 'tuple-index'):
+            self.ts[:, 2]
+        with tm.assertRaisesRegexp(ValueError, 'tuple-index'):
+            self.ts[:, 2] = 2
 
         # weird lists. [slice(0, 5)] will work but not two slices
         result = self.ts[[slice(None, 5)]]