Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammatory condition similar to human autoimmune hepatitis. We investigated the role of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice by a single injection of ConA. Recombinant murine IL-12 administered 24 hours and 1 hour prior to ConA exacerbated both transaminase activities in plasma and histologic signs of hepatitis. These markers of liver injury were significantly reduced by prophylactic, but not therapeutic treatment with anti–IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti–IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interferon gamma (IFN-γ) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti–IL-12 mAb/ConA-treated mice. Anti–IFN-γ mAb also impeded the appearance of IL-12/ConA-induced hepatitis. Thus, IL-12–induced production of IFN-γ might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p40–deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.