diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index d3e75d43c6bd7..081f87078d9c9 100755
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1564,6 +1564,17 @@ def _convert_to_indexer(self, key, axis: int, is_setter: bool = False):
     # -------------------------------------------------------------------
 
     def _setitem_with_indexer(self, indexer, value):
+        """
+        _setitem_with_indexer is for setting values on a Series/DataFrame
+        using positional indexers.
+
+        If the relevant keys are not present, the Series/DataFrame may be
+        expanded.
+
+        This method is currently broken when dealing with non-unique Indexes,
+        since it goes from positional indexers back to labels when calling
+        BlockManager methods, see GH#12991, GH#22046, GH#15686.
+        """
 
         # also has the side effect of consolidating in-place
         from pandas import Series
@@ -1678,24 +1689,19 @@ def _setitem_with_indexer(self, indexer, value):
                 info_idx = [info_idx]
             labels = item_labels[info_idx]
 
-            # if we have a partial multiindex, then need to adjust the plane
-            # indexer here
-            if len(labels) == 1 and isinstance(
-                self.obj[labels[0]].axes[0], ABCMultiIndex
-            ):
+            if len(labels) == 1:
+                # We can operate on a single column
                 item = labels[0]
-                obj = self.obj[item]
-                index = obj.index
-                idx = indexer[:info_axis][0]
+                idx = indexer[0]
 
-                plane_indexer = tuple([idx]) + indexer[info_axis + 1 :]
-                lplane_indexer = length_of_indexer(plane_indexer[0], index)
+                plane_indexer = tuple([idx])
+                lplane_indexer = length_of_indexer(plane_indexer[0], self.obj.index)
                 # lplane_indexer gives the expected length of obj[idx]
 
                 # require that we are setting the right number of values that
                 # we are indexing
-                if is_list_like_indexer(value) and lplane_indexer != len(value):
-
+                if is_list_like_indexer(value) and 0 != lplane_indexer != len(value):
+                    # Exclude zero-len for e.g. boolean masking that is all-false
                     raise ValueError(
                         "cannot set using a multi-index "
                         "selection indexer with a different "
@@ -1704,12 +1710,11 @@ def _setitem_with_indexer(self, indexer, value):
 
             # non-mi
             else:
-                plane_indexer = indexer[:info_axis] + indexer[info_axis + 1 :]
-                plane_axis = self.obj.axes[:info_axis][0]
-                lplane_indexer = length_of_indexer(plane_indexer[0], plane_axis)
+                plane_indexer = indexer[:1]
+                lplane_indexer = length_of_indexer(plane_indexer[0], self.obj.index)
 
             def setter(item, v):
-                s = self.obj[item]
+                ser = self.obj[item]
                 pi = plane_indexer[0] if lplane_indexer == 1 else plane_indexer
 
                 # perform the equivalent of a setitem on the info axis
@@ -1721,16 +1726,16 @@ def setter(item, v):
                     com.is_null_slice(idx) or com.is_full_slice(idx, len(self.obj))
                     for idx in pi
                 ):
-                    s = v
+                    ser = v
                 else:
                     # set the item, possibly having a dtype change
-                    s._consolidate_inplace()
-                    s = s.copy()
-                    s._data = s._data.setitem(indexer=pi, value=v)
-                    s._maybe_update_cacher(clear=True)
+                    ser._consolidate_inplace()
+                    ser = ser.copy()
+                    ser._data = ser._data.setitem(indexer=pi, value=v)
+                    ser._maybe_update_cacher(clear=True)
 
                 # reset the sliced object if unique
-                self.obj[item] = s
+                self.obj[item] = ser
 
             # we need an iterable, with a ndim of at least 1
             # eg. don't pass through np.array(0)