Encephalomyocarditis (EMC) virus induction of diabetes mellitus in mice has proven to be an excellent experimental model for the pathogenesis of viral disease. In SJL and DBA/2 mice, diabetes results exclusively from the infection and damage of beta cells by the virus. In addition, in BALB/cBy mice subclinical beta cell damage caused by the virus is followed by autoimmune beta cell destruction, which results in hyperglycemia. Studies of two closely related plaque variants (EMC-D and EMC-B) selected from the M strain of EMC virus revealed differences in the interferon response associated with viral infection. The EMC-D variant causes diabetes in infected SJL mice by direct beta cell destruction. Infection with EMC-B does not cause diabetes and interferes with the production of diabetes by EMC-D due to the greater ability of EMC-B than of EMC-D to induce interferon in mice. Circulating interferon has a greater effect on inhibition of viral replication because local interferon production is amplified in interferon-primed cells infected with EMC-B. These properties are determined by the interferon-inducing particle (Ifp+) phenotype of EMC-B and the Ifp- phenotype of EMC-D.