In several models of inflammation, including collagen‐induced arthritis (CIA), the disease‐promoting effect of IL‐12 has been attributed to its well‐known ability to produce IFN‐γ. However, IFN‐γ receptor knockout (IFN‐γ R KO) mice of the DBA/1 strain have been reported to be more susceptible to CIA than corresponding wild‐type mice, indicating the existence of an IFN‐γ‐mediated protective pathway in this model. In the present study the development of CIA was found to be completely prevented by pretreatment with a neutralizing anti‐IL‐12 antibody, not only in wild‐type, but significantly also in IFN‐γ R KO mice. In both strains of mice, the protective effect of anti‐IL‐12 was associated with lower production of anti‐collagen type II antibodies. In vivo stimulation with anti‐CD3 antibody in arthritic IFN‐γ R KO mice resulted in production of higher levels of circulating IFN‐γ, TNF and IL‐2 than in corresponding control mice that had not received the arthritis‐inducing immunization. This was not the case in arthritis‐developing wild‐type mice. Furthermore, the protective effect of anti‐IL‐12 antibody in mutant, but not in wild‐type mice, was associated with lower circulating IFN‐γ, TNF and IL‐2 and higher IL‐4 and IL‐5 cytokine levels following an anti‐CD3 challenge. The data indicate that IL‐12 promotes the development of arthritis independently of its ability to induce or favor production of IFN‐γ. In fact, any IFN‐γ produced in the course of the disease process rather exerts a protective effect. Furthermore, our study suggests that, in the absence of a functional IFN‐γ system, endogenous IL‐12 exerts its disease‐promoting effect by favoring production of other Th1‐associated cytokines (IL‐2 and TNF), by inhibiting development of IL‐4‐ and IL‐5‐producing T cells and by stimulating production of anti‐collagen autoantibodies.