Previous studies of complement activation in serum by urate crystals have not supported a role for immunoglobulins (Naff and Byers, J. Lab. Clin. Med. 81:797, 1973). The recent demonstration by Kozin and McCarty (J. Lab. Clin. Med. 89:1314, 1977) of adsorption of IgG to urate crystals prompted us to reexamine this question. Addition of urate crystals (10 mg per ml.) to hypogamma-globulinemic serum reduced hemolytic activity only slightly but caused virtually complete depletion from normal serum. Addition of 7S IgG (10 mg per ml) but not IgA (10 mg/ml) nor IgM (10 mg/ml) restored the ability of such serum to demonstrate depletion of C activity by urate crystals. Urate crystals were able to inactivate C3 in normal human serum but not in C2 deficient human serum nor in C4 deficient guinea pig serum. This effect is mediated primarily through the classical pathway.