IL‐18 is an important cofactor in Th1 immune responses and it has additional roles in inflammation. Recent reports suggest the contribution of IL‐18 to immune responses may vary between mouse strains and immune contexts. We investigated the contribution of IL‐18 to T‐cell activation and joint inflammation in Ag‐induced arthritis (AIA) in C57Bl/6 mice. AIA and cutaneous delayed‐type hypersensitivity (DTH) reactions were induced in wild‐type (WT) and IL‐18^−/− C57Bl/6 mice, and Ag‐specific T‐cell proliferation and IFN‐γ and IL‐4 production were measured. The humoral immune response was measured as serum antibody to the disease‐initiating Ag, methylated BSA (mBSA). Splenocyte production of IL‐6 was measured by ELISA. To confirm the dependence of this model on Th1‐cell‐mediated immunity, IL‐12p40^−/− mice were similarly studied. WT mice developed synovitis, joint effusion, cartilage destruction and bone damage associated with induction of DTH, and in vitro Ag‐specific T‐cell proliferation and IFN‐γ production. Unexpectedly, IL‐18^−/− mice developed AIA and indices of T‐cell activation were similar to those of WT mice. In contrast, IL‐12p40^−/− mice did not develop AIA, DTH or T‐cell activation. WT and IL‐18^−/− mice, but not IL‐12p40^−/− mice, developed significantly increased serum antibody to mBSA compared with naive controls. WT and IL‐18^−/− splenocytes produced high levels of IL‐6, whereas IL‐12p40^−/− cells had significantly lower IL‐6 production compared with both. In conclusion, IL‐18 is redundant both as a Th1 response cofactor and inflammatory cytokine, whereas IL‐12p40^−/− is a key cytokine, in AIA in C57Bl/6 mice.