A possible contribution of the immune system to the pathogenesis of virus-induced diabetes mellitus was investigated using the D-variant of encephalomyocarditis (EMC-D) virus. Studies on the F1 and backcross progeny of susceptible and resistant strains of mice gave no suggestion of a linkage between susceptibility and the major histocompatibility locus. Immunosuppression by antilymphocyte serum did not prevent the induction of EMC-D-induced diabetes. Athymic nude mice infected with EMC-D virus showed a nearly identical diabetogenic response as comparedwith heterozygous litter mates. Passive transfer of lymphocytes from mice made diabetic with EMC-D virus into normal mice failed to produce diabetes. From these and other studies, we conclude that the development of EMC-Dinduced diabetes is due to the direct destruction of β-cells by the virus and that the contribution of the immune response to the pathogenesis of this disease is, at the most, minor.