diff --git a/doc/source/whatsnew/v0.21.0.txt b/doc/source/whatsnew/v0.21.0.txt
index c63d4575bac43..9f352f907c0c6 100644
--- a/doc/source/whatsnew/v0.21.0.txt
+++ b/doc/source/whatsnew/v0.21.0.txt
@@ -204,3 +204,4 @@ Categorical
 Other
 ^^^^^
 - Bug in :func:`eval` where the ``inplace`` parameter was being incorrectly handled (:issue:`16732`)
+- Bug when using :func:`isin` on a large object series and large comparison array (:issue:`16012`)
diff --git a/pandas/core/algorithms.py b/pandas/core/algorithms.py
index b490bf787a037..4ee2c54000fb6 100644
--- a/pandas/core/algorithms.py
+++ b/pandas/core/algorithms.py
@@ -402,7 +402,10 @@ def isin(comps, values):
     # work-around for numpy < 1.8 and comparisions on py3
     # faster for larger cases to use np.in1d
     f = lambda x, y: htable.ismember_object(x, values)
-    if (_np_version_under1p8 and compat.PY3) or len(comps) > 1000000:
+    # GH16012
+    # Ensure np.in1d doesn't get object types or it *may* throw an exception
+    if ((_np_version_under1p8 and compat.PY3) or len(comps) > 1000000 and
+       not is_object_dtype(comps)):
         f = lambda x, y: np.in1d(x, y)
     elif is_integer_dtype(comps):
         try:
diff --git a/pandas/tests/series/test_analytics.py b/pandas/tests/series/test_analytics.py
index 749af1c56a7f0..ab75dbf1b51cc 100644
--- a/pandas/tests/series/test_analytics.py
+++ b/pandas/tests/series/test_analytics.py
@@ -1092,6 +1092,18 @@ def test_isin(self):
         expected = Series([True, False, True, False, False, False, True, True])
         assert_series_equal(result, expected)
 
+        # GH: 16012
+        # This specific issue has to have a series over 1e6 in len, but the
+        # comparison array (in_list) must be large enough so that numpy doesn't
+        # do a manual masking trick that will avoid this issue altogether
+        s = Series(list('abcdefghijk' * 10 ** 5))
+        # If numpy doesn't do the manual comparison/mask, these
+        # unorderable mixed types are what cause the exception in numpy
+        in_list = [-1, 'a', 'b', 'G', 'Y', 'Z', 'E',
+                   'K', 'E', 'S', 'I', 'R', 'R'] * 6
+
+        assert s.isin(in_list).sum() == 200000
+
     def test_isin_with_string_scalar(self):
         # GH4763
         s = Series(['A', 'B', 'C', 'a', 'B', 'B', 'A', 'C'])