The distribution of Met-enkephalin (Enk) and substance P (SP) was examined in the striatum of Huntington's disease (HD) patients using immunoperoxidase techniques. Both Enk- and SP-like immunoreactivities (ir) were strikingly diminished in the dorsal caudate nucleus and putamen, while patchy staining persisted in the ventral putamen and nucleus accumbens. This was in sharp contrast to the patch-matrix pattern of acetylcholinesterase (AChE) staining which persisted throughout the entire striatum in HD. The regional loss of Enk- and SP-ir parallels the pattern of neuronal depletion in HD. The disparity between AChE staining and Enk- and SP-ir in HD suggests that AChE-positive neurons or fibers are resistant to the destructive process in areas where intrinsic neuronal populations are depleted.