This report concerns the topographic immunohistochemical analysis of the putamen, globus pallidus (GP) and substantia nigra (SN) of two patients with adult-onset motor neuron disease with basophilic inclusions (MND/BIs), seven patients with sporadic classic amyotrophic lateral sclerosis (sporadic ALS) and five neurologically normal individuals. The striatal efferent terminals of the GP and SN were visualized immunohistochemically using antibodies to met-enkephalin (MEnk) and substance P (SP). In specimens from patients with sporadic ALS and normal subjects there was intense immunostaining for MEnk and SP throughout the external and internal segments of the GP, respectively. By contrast, a marked reduction of MEnk- and SP-positive striatal efferents was seen in the ventrocaudal portions of both GP segments from the MND/BIs patients. Moreover, while MEnk-positive striosomes was readily detected in the putamen of normals and sporadic ALS patients, there was significant reduction in MEnk immunoreactivity, and no evidence of striosomal organization in the putamen of MND/BIs patients. In addition, whereas the SN of patients with sporadic ALS expressed SP, the ventrolateral SN portion of the MND/BIs patient tested had reduced immunoreactivity. The present findings on patients with MND/BIs may represent a reflection of the topographic striatum degeneration in this disease and appear to provide additional evidence for the heterogeneity of MND.