Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of IDDM, but it is not clear which form, IL-1α or IL-1β, is predominantly implicated. In this study, we have evaluated the contribution of IL-1β by treating diabetes-prone nonobese diabetic (NOD) mice with specific neutralizing antibodies. First, we assessed the neutralizing potential of these antibodies in C57BL/6 mice under acute septic shock by measuring IL-1β in sera 4 h after lipopolysaccharide injection. One milligram and 0.1 mg of anti–IL-1β antibodies (Abs) were capable of neutralizing the IL-1β produced, and the effect persisted for at least 5 days. Second, we evaluated the role of IL-1β in the cyclophosphamide (CY)-accelerated model of diabetes. Nondiabetic male NOD mice were injected with 200 mg/kg CY and treated twice weekly with anti–IL-1β Ab. The incidence of diabetes reached 76 and 100% in the control groups treated with 0.25 and 0.1 mg rabbit IgG, respectively. In contrast, only 34% of mice treated with 0.25 mg of anti–IL-1β Ab became diabetic. In the group treated with 0.1 mg of anti–IL-1β Ab, 89% of the mice became diabetic in the same period of time, demonstrating that the protective effect was dose dependent. Our results show that IL-1β is a critical effector molecule in this model of IDDM and that its specific inhibition could be an attractive target for therapeutic intervention.