The demonstration of a genetic linkage between the copper-zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patients with sporadic amyotrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative in situ hybridization technique. There were no significant differences between the amounts of SOD1 messenger RNA observed in patients with sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levels of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relationship between the SOD1 gene and the pathogenesis of amyotrophic lateral sclerosis.