Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-gamma plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-gamma production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Faslpr strain deficient in IL-18Ralpha. Compared with the wild-type strain, IL-18Ralpha-deficient MRL-Faslpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-gamma, TNF-alpha, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Faslpr mouse disease were diminished in IL-18Ralpha-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Ralpha signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.