Cell-mediated immunity to poliovirus was demonstrated in 21 of 33 patients suffering from amyotrophic lateral sclerosis (ALS), whereas no response to poliovirus was found in patients suffering from other neurologic disorders or in healthy controls. Three of the severe bulbar cases produced a migration inhibition factor (MIF) in the presence of poliovirus, although skin tests to common antigens were negative. An increased incidence (46 percent) of HLA-A3 was found in patients with amyotrophic lateral sclerosis. Nine of the 13 patients with HLA-A3 antigen also had a positive index of MIF to poliovirus. These findings suggest a strong linkage between HLA-A3 and poliovirus in the pathogenesis of amyotrophic lateral sclerosis.