The repeated administration of interferon (IFN) or an IFN inducer reduced the development of diabetes in mice infected with the D variant of encephalomyocarditis (EMC) virus. Mice treated with the IFN inducer had less infectious virus, fewer pathologic changes, and higher concentrations of immunoreactive insulin in the islets of Langerhans in comparison with untreated mice. Antibody to mouse IFN (MuIFN) suppressed circulating IFN in mice infected with the B variant of EMC virus. Mice treated with antibody to MuIFN had four times more infected islet cells and 10 times more infectious virus in the pancreas compared with untreated mice. Of the surviving animals treated with antibody to MuIFN, ∼40% developed mild diabetes whereas none of the mice developed diabetes when infected with the B variant of EMC virus alone. The IFN system is an important determinant of the outcome in EMC virus-induced diabetes in mice.