Recognition of immune complexes in glomeruli by activator Fcγ receptors (FcγRI and FcγRIII) is an important step in the development of glomerulonephritis. The low-affinity receptor (FcγRIII) has previously been shown to be important in passive heterologous immune complex glomerulonephritis. However, most forms of human glomerulonephritis involve an active immune response, and the relative importance of FcγRI (high-affinity receptor) and FcγRIII in an active model of glomerulonephritis is not known. We have now studied accelerated nephrotoxic nephritis in FcγRIII−/− mice and FcγRI/III double-deficient mice, and compared them with matched wild-type controls and FcRγ chain-deficient (FcRγ−/−) mice. Mice were immunized against sheep IgG and injected with sheep anti-mouse glomerular basement membrane antibody 5 days later. Both FcγRI/III double-deficient mice and FcRγ−/− mice were strongly protected from renal injury. In contrast, FcγRIII−/− mice developed substantial nephritis, although there was a dose-dependent partial protection from glomerular crescents and thrombosis. Despite this histological protection from injury, the macrophage infiltrate was not reduced, implying a dissociation of macrophage accumulation from activation in the absence of activatory FcγRIII. Therefore, both FcγRI and FcγRIII play a role in this active model of glomerulonephritis, because both had to be deficient to protect markedly from disease.