Two classes of receptors for IgG, FcγRIIa and FcγRIIIb, both of which exist in two allelic forms, are expressed on human neutrophils. Neutrophils from normal donors, homozygous for the different allelic phenotypes of FcyRIIIb, have significantly different levels of Fcγ receptor-mediated phagocytosis of IgG-opsonized erythrocytes (EA). However, the observation that FcyRIIIb mediates phagocytosis of specific mAb-targeted erythrocytes poorly suggests that this receptor may influence EA internalization by FcγRIIa in an allele-sensitive fashion. Donors homozygous for the NA1 allele of FcγRIIIb showed greater activation of FcγRIIa after FcγRIIIb cross-linking than donors homozygous for the NA2 allele of FcγRIIIb. This increase in receptor-specific internalization reflects both an increase in ligand binding by FcyRIIa and an increase in internalization efficiency of targets bound. Activation of FcγRIIa by FcγRIIIb is transferable by supernatants from activated cells and is blocked by inhibitors of reactive oxygen species and the H2O2-myeloperoxidase-chloride system and by serine protease inhibitors. Thus, cross-linking of FcγRIIIb, which leads to neutrophil degranulation and the generation of reactive oxygen intermediates, in turn alters FcγRIIa avidity and efficiency. These oxidant-mediated changes in FcγRIIa function provide a novel mechanism for receptors to collaborate in both an autocrine and paracrine fashion. The allele sensitivity of these effects suggests that Fcγ receptor polymorphisms may be inherited disease susceptibility factors in host defense against infection and in the development of autoimmunity.