T helper type 1 (T(H)1) lymphocytes are considered to be the main pathogenic cell type responsible for organ-specific autoimmune inflammation. As interleukin 18 (IL-18) is a cofactor with IL-12 in promoting T(H)1 cell development, we examined the function of IL-18 and its receptor, IL-18R, in autoimmune central nervous system inflammation. Similar to IL-12-deficient mice, IL-18-deficient mice were susceptible to experimental autoimmune encephalomyelitis. In contrast, IL-18R alpha-deficient mice were resistant to experimental autoimmune encephalomyelitis, indicating involvement of an IL-18R alpha ligand other than IL-18 with encephalitogenic properties. Moreover, engagement of IL-18R alpha on antigen-presenting cells was required for the generation of pathogenic IL-17-producing T helper cells. Thus, IL-18 and T(H)1 cells are dispensable, whereas IL-18R alpha and IL-17-producing T helper cells are required, for autoimmune central nervous system inflammation.