A number of studies and clinical case reports have implicated interferon (IFN)-α as a potential mediator of type 1 diabetes pathogenesis. Administration of polyinosinic:polycytidylic acid (poly I:C), a mimic of viral double-stranded RNA, induces diabetes in C57BL/6 mice expressing the B7.1 costimulatory molecule in islets. We investigated the potential role of IFN-α in this disease model. The quantitative correlation between IFN-α levels and time to diabetes, diabetes prevention with anti–IFN-α antibody, and ability of IFN-α itself to induce diabetes are consistent with the hypothesis that poly I:C in this model acts by induction of IFN-α in a genetically susceptible host. Numerous recent studies highlight the importance of the innate immune system and toll receptors in determining adaptive immune responses, and we speculate that for type 1 diabetes, viral and other environmental factors may act through induction of IFNs.