Recognition of immune complexes in glomeruli by activator Fcgamma receptors (FcgammaRI and FcgammaRIII) is an important step in the development of glomerulonephritis. The low-affinity receptor (FcgammaRIII) 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 FcgammaRI (high-affinity receptor) and FcgammaRIII in an active model of glomerulonephritis is not known. We have now studied accelerated nephrotoxic nephritis in FcgammaRIII-/- mice and FcgammaRI/III double-deficient mice, and compared them with matched wild-type controls and FcRgamma chain-deficient (FcRgamma-/-) mice. Mice were immunized against sheep IgG and injected with sheep anti-mouse glomerular basement membrane antibody 5 days later. Both FcgammaRI/III double-deficient mice and FcRgamma-/- mice were strongly protected from renal injury. In contrast, FcgammaRIII-/- 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 FcgammaRIII. Therefore, both FcgammaRI and FcgammaRIII play a role in this active model of glomerulonephritis, because both had to be deficient to protect markedly from disease.