Collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis, is induced in DBA/1 (H-2q) mice following immunization with type II collagen (CII) in CFA. Since we have previously shown that IFN-gamma exerts a biphasic effect during the evolution of CIA in DBA/1 mice, we analyzed the development of this disease in mice with a disruption of the IFN-gamma receptor gene (IFN-gammaR(0/0)). Mutant mice were interbred with the DBA/1 strain to yield IFN-gammaR(0/0) mice expressing the H-2q haplotype. In three consecutive experiments, IFN-gammaR(0/0) male mice were found to exhibit severe clinical and histologic arthritis with an average incidence of 88.5 vs 94.1% for the wild DBA/1 strain. Notably, onset of clinical symptoms occurred significantly earlier than in DBA/1 mice. Although of a lower magnitude than in males, CIA also developed early in IFN-gammaR(0/0) female mice and with higher clinical severity than in control DBA/1 females. Immunization of knockout mice with CII resulted in the generation of CII-specific T cells belonging to the Th1 phenotype that recognize the same immunodominant peptides as do DBA/1 mice. CIA in IFN-gammaR(0/0) mice was associated with a down-regulation of the CII-specific IgG response, and this impairment was essentially due to a strong reduction of Abs of the IgG2a isotype. Taken together, our findings provide evidence that IFN-gammaR deficiency in DBA/1 mice leads to the occurrence of severe CIA with an accelerated onset compared with that in wild-type mice, indicating that the proinflammatory action of IFN-gamma has been bypassed in the IFN-gammaR(0/0) mice.