Introduction of heterologous anti–glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor FcγRIV and its inhibitory receptor counterpart, FcγRIIB. Blocking FcγRIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous γ-globulin (IVIG) to down-regulate FcγRIV while up-regulating FcγRIIB, protects mice from fatal disease. In the absence of FcγRIIB, IVIG is not protective; this indicates that reduced FcγRIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcγRs in renal disease.