Antibodies to sulfatide have been reported in various demyelinating peripheral polyneuropathies. We have investigated the diagnostic value of these antibodies in leprosy. Anti-sulfatide IgM in leprosy patients was not significantly elevated. High anti-sulfatide IgG titers were observed in individuals from endemic areas, irrespective of their leprosy status, while western European controls were negative. No significant correlation was found between IgM or IgG antibody titers and leprosy classification, although multibacillary patients had higher anti-sulfatide IgM titers than paucibacillary patients. In addition, 23 patients developing leprosy reactions were followed longitudinally. Antibody titers in these patients fluctuated slightly during the follow-up period. There was no association with the occurrence of leprosy reactions or treatment. Thus, IgG titers against sulfatides are high in both leprosy patients and healthy controls in endemic areas, whereas such antibodies are not found in western European controls, suggesting that these antibodies are induced by environmental factors, such as microorganisms.