The marked atrophy of the striatum seen in Huntington's disease (HD) is largely due to a massive neuronal loss that affects the striatal projection neurons more severely than the local circuit neurons. We recently reported the existence of a new class of interneurons characterized by their immunoreactivity for the calcium-binding protein calretinin in the human striatum. In the present immunohistochemical study, we compared the distribution and relative density of the calretinin-expressing interneurons in the striata of four normal individuals and four patients with HD (grade 1 to 3). The population of calretinin-containing interneurons comprised (a) a small subset of large (17- to 44-microns), multipolar neurons with five to seven long, aspiny, and highly branched dendrites and (b) a large number of medium-sized (8- to 18-microns), round-to-oval neurons with two to three long, varicose, and poorly branched dendrites. Both types of chemospecific neurons occurred throughout the striatum in all specimens examined, but the density of the medium-sized neurons was much higher in patients with HD than in controls. A quantitative analysis showed a significant (p < 0.01) twofold increase in the density of the striatal medium-sized neurons and a similar decrease in the density of the large neurons in patients with HD compared with controls. This differential effect on the densities of the two types of interneurons suggests that calretinin may protect the medium-sized but not the large neurons against neurodegeneration in HD.