Alpha-1 Antitrypsin, the major circulating protease inhibitor, has more than thirty alleles that can be identified by electrophoresis. In addition to its role as a protease inhibitor, alpha-1 antitrypsin may regulate the immune response. As there is evidence that both the inflammatory polyneuropathies and multiple sclerosis have an immune basis, and that genetic factors influence susceptibility, we have determined the alpha-1 antitrypsin phenotypes (protease inhibitor types) of 63 patients with Guillain-Barré syndrome, 52 patients with chronic inflammatory demyelinating polyneuropathy, and 178 patients with multiple sclerosis. In all 3 groups there was a significant increase in the proportion of patients with the protease inhibitor type M3 allele.