MRL/lpr mice develop lymphoproliferation and accelerated autoimmune glomerulonephritis from which they ultimately die. To investigate the role of IFN-gamma in the manifestation of the disease, we generated MRL/lpr mice lacking the IFN-gamma receptor (MRL/lpr gammaR -/-). The absence of IFN-gamma signaling had no effect on generalized lymphoproliferation, expansion of CD4- CD8- double-negative T cells, or hypergammaglobulinemia. By contrast, glomerulonephritis as detected by proteinuria and histology was absent in MRL/lpr gammaR -/- mice. While serum IgG1 anti-dsDNA Abs were increased in all three strains of MRL/lpr mice (gammaR +/+, +/-, -/-), those of the IgG2a and IgG3 isotypes were low in MRL/lpr gammaR -/- mice. Immune complexes and C3 deposition were dramatically reduced in the glomerular capillaries of MRL/lpr gammaR -/- mice compared with MRL/lpr gammaR +/+ and +/- mice. Therefore, IFN-gamma plays a key regulatory role in the development of nephritis in MRL/lpr mice. Low levels of IFN-gamma-dependent IgG2a and IgG3 autoantibodies in MRL/lpr gammaR -/- mice might protect them from the pathogenic features of IgG3 cryoglobulins and complement-activating IgG2a and IgG3.