The distribution of NADPH diaphorase staining in the human basal ganglia was compared in five cases who were neurologically normal with five cases who died with Huntington's disease. The normal cases showed an intense staining for NADPH diaphorase throughout all regions of the neuropil in the striatum (caudate nucleus, putamen and nucleus accumbens); the staining in the neuropil was largely homogeneous although a heterogeneous distribution was evident at rostral levels of the head of the caudate nucleus and in the nucleus accumbens where patches of reduced staining aligned with acetylcholinesterase-poor regions. The globus pallidus showed a moderately intense homogeneous pattern of staining for NADPH diaphorase. In comparison with control cases, sections of the striatum from the five cases with Huntington's disease showed a dramatic decrease in the intensity of NADPH diaphorase staining in the neuropil, especially in the caudate nucleus and putamen. In cases of early Huntington's disease where no discernible loss of neurons was seen [grade 0 using the grading criteria of Vonsatell et al. (1985) J. Neuropath. exp. Neurol. 44, 559-577], there was a marked heterogeneous pattern of staining in the caudate nucleus and putamen showing a patchy loss of NADPH diaphorase in the neuropil. This resulted in clearly delineated islands of greatly reduced staining surrounded by a matrix of moderately reduced staining; the patches of greatly reduced staining corresponded with acetylcholinesterase-poor striosomes. In cases of more advanced neuropathology (grades 1 and 2) the loss of NADPH diaphorase staining in the neuropil was even more marked, affecting both acetylcholinesterase-poor and acetylcholinesterase-rich regions of the caudate nucleus and putamen and resulting in an almost homogeneous loss of staining in these striatal regions. Despite this marked loss of staining in the neuropil, the numbers of NADPH diaphorase-stained neuronal somata in the striatum in Huntington's cases appeared comparable to those in the control cases. In the globus pallidus of one of the advanced Huntington's disease cases there appeared to be a minimal loss of NADPH diaphorase staining; however, staining in the other regions of the brain which were examined was similar to that in the control cases. These findings demonstrate a progressive compartmental loss of NADPH diaphorase in the neuropil of the human striatum in Huntington's disease which correlates with the extent of neurodegeneration; early in the disease the loss of neuropil staining is first evident in the striosome compartment, then followed by an additional loss in the matrix compartment in more advanced cases of the disease.(ABSTRACT TRUNCATED AT 400 WORDS)