We have studied the effects of either exogenously-administered interferon (IFN-)γ or of a nonimmunogenic mouse IFN-γ receptor-Immunoglobulin (IFN-γR-Ig) fusion protein on the development of Concanavalin (Con)A-induced hepatitis in NMRI mice. PBS-treated control mice injected with 20mg/kg ConA developed classical serological and histological signs of hepatitis with elevation of transaminases in the blood and infiltration of the liver by mononuclear cells and neutrophils. Treating the mice with rat IFN-γ 24h prior to and 1h after ConA-challenge markedly exacerbated these signs of hepatitis in a dose-dependent fashion. Moreover, mice injected with lower, non hepatitogenic, doses of ConA (10, 5mg/kg) became fully susceptible to develop hepatitis upon similar treatment with IFN-γ. Concordantly, ConA-induced hepatitis was abrogated by either IFN-γR-Ig fusion protein or anti-IFN-γ mAb. These data provide further evidence for the central pathogenetic role of endogenous IFN-γ in ConA-induced hepatitis and demonstrate the feasibility to prevent disease development by means of a non immunogenic IFN-γR-Ig fusion protein.