The BB rat spontaneously develops an insulin-dependent diabetes mellitus (IDDM) that closely resembles this disease in man. The pathogenesis involves autoimmune destruction of pancreatic beta-cells. In the present study, inoculation of diabetes-prone BB rats at 30 days of age with a lymphotropic variant of lymphocytic choriomeningitis virus significantly reduced the incidence of diabetes. Such virus-inoculated, diabetes-free rats had normal levels of pancreatic insulin and little or no mononuclear cell infiltration in the islets. Virus was recovered from lymphocytes by cocultivation with permissive cells. In contrast, virus was not detected in a wide variety of organs, indicating that infection in BB rats was primarily lymphotropic. PBL analyzed by FACS and monoclonal markers showed a marked reduction of pan-T. Th, and T suppressor/cytotoxic lymphocyte subsets restricted to 4 and 7 days after infection when compared with numbers of lymphocytes in uninoculated diabetes-prone rats. To prevent IDDM, replicating virus was required, because the expected incidence of IDDM in diabetes prone rats inoculated with UV-inactivated virus was equivalent to that of untreated animals. These results suggest that a virus can suppress the autoimmune response that would otherwise have caused IDDM and may be useful as a probe in dissecting the molecular basis of this autoimmune disorder.