We carried out an immunohistochemical investigation of the spinal cords of 15 patients with sporadic amyotrophic lateral sclerosis (ALS), using antibodies to inducible nitric oxide synthase (iNOS) and nitrotyrosine; our purpose was to search for a possible role of increased oxidative damage in the motor system that may contribute to the neurodegenerative process in this disease. Specimens from 16 patients without any neurological disease served as controls. In the controls, normal-appearing neurons and their dendrites were negatively immunostained for iNOS. In the ALS patients, most of normal-appearing anterior horn neurons did not show iNOS immunoreactivity either in the perikarya or in their dendrites. However, many of the degenerated neurons showing central chromatolysis or simple atrophy demonstrated focally or diffusely positive iNOS immunoreactivity within the perikarya and their neuronal processes. In the neuropil of the anterior horns, the reactive astrocytes were more intensely immunostained for iNOS as compared with the controls. Some of the swollen proximal axons (spheroids) were focally or diffusely immunostained by the antibody. The corticospinal tracts demonstrated positive iNOS immunoreactivity of proliferated reactive astrocytes. The immunostaining pattern of nitrotyrosine in the anterior horn neurons of the spinal cord was similar to that of iNOS. These findings suggest that selective nitric oxide-mediated oxidative damage in the motor system plays a part in the pathomechanism of the neuronal degeneration in the spinal cord of sporadic ALS.