By virtue of its ability to couple the BCR to an inhibitory pathway, FcγRIIB can potentially determine the fate of B cells upon IgG immune complex engagement. We now provide evidence for FcγRIIB as a component of a peripheral tolerance pathway with the observation that RIIB^−/− mice develop autoantibodies and autoimmune glomerulonephritis in a strain-dependent fashion. Transfer of the autoimmune phenotype is associated with the presence of donor RIIB^−/− B cells, with the RIIB^+/+ myeloid cells primarily derived from the recipient. These results suggest that deficiency of RIIB on B cells leads to autoimmune disease in specific genetic backgrounds, thus identifying it as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.