IL-1 is a pro-inflammatory cytokine that plays an important role in inflammation and host responses to infection. We have previously shown that imbalances in the IL-1 and IL-1R antagonist (IL-1Ra) system cause the development of inflammatory diseases. To explore the role of the IL-1/IL-1Ra system in autoimmune disease, we analyzed myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in mice bearing targeted disruptions of the IL-1α, IL-1β, IL-1α and IL-1β (IL-1) or IL-1Ra genes. IL-1α/β double-deficient (IL-1^−/−) mice exhibited significant resistance to EAE induction with a significant reduction in disease severity, while IL-1α^−/− or IL-1β^−/− mice developed EAE in a manner similar to wild-type mice. IL-1Ra^−/− mice also developed MOG-induced EAE normally with pertussis toxin (PTx) administration. In contrast to wild-type mice, however, these mice were highly susceptible to EAE induction in the absence of PTx administration. We found that both IFN-γ and IL-17 production and proliferation were reduced in IL-1^−/− T cells upon stimulation with MOG, while IFN-γ, IL-17 and tumor necrosis factor-α production and proliferation were enhanced in IL-1Ra^−/− T cells. These observations suggest that the IL-1/IL-1Ra system is crucial for auto-antigen-specific T cell induction and contributes to the development of EAE.