The C3b receptor of human erythrocytes, neutrophils, monocytes, all mature B cells, a subpopulation of T cells, and glomerular podocytes is a single chain glycoprotein that exists in two allotypic forms having Mr's of approximately 250,000 (F) and 260,000 (S). The number of receptors present on erythrocytes varies by eight-fold among different individuals and is genetically regulated by two codominant alleles that are distinct from the alleles determining the structural polymorphism. The number of receptors expressed by neutrophils is subject to rapid increases from 5000 per cell to 40,000 per cell by exposure to nanomolar concentrations of C5adesArg, in vitro, and a similar mechanism is probably the basis for observing increased receptor expression on neutrophils in patients undergoing hemodialysis. Cytoskeletal association of the C3b receptor on monocytes and neutrophils is suggested by experiments demonstrating receptor-mediated phagocytosis, adsorptive endocytosis through coated pits, and restricted lateral diffusion, and by the reciprocal co-redistribution of cross-linked C3b and Fc receptors, and the detergent-insolubility of cross-linked C3b receptors. The factor H-like cofactor activity of the C3b receptor promotes the cleavage of bound C3b to iC3b, C3c and C3d, g, reactions that may enhance the clearance of circulating immune complexes and the generation of ligands for CR2 and CR3. The inherited partial deficiency of erythrocyte C3b receptors in patients with SLE, and the absence of glomerular C3b receptors in these patients with proliferative glomerulonephritis may contribute to systemic and organ-specific abnormalities in the clearance of immune complexes that contribute to the pathogenesis of this disease.