The reticuloendothelial system is thought to play an important role in removing immune complexes and other immunologically active substances from the circulation via interaction with specific cell-surface receptors. The function of the reticuloendothelial system in humans with autoimmune diseases was studied in vivo by measuring the rate of removal of IgG-coated, radio-labeled autologous erythrocytes. Such cells are removed by phagocytic cells of the spleen, and the process depends on the presence of an intact IgG Fc fragment. Studies in patients with active systemic lupus erythematosus show a profound defect in Fc-receptor-specific clearance that correlates with disease activity. Patients with other autoimmune diseases have defects in Fc receptor functional activity when their illness is characterized by tissue deposition of immune complexes. Normal patients with HLA-B8/DRw3, an HLA type associated with an increased incidence of autoimmune disease, also have an increased incidence of defective Fc receptor-specific functional activity, suggesting that this defect may predispose patients with this haplotype to develop manifestations of immune complex-mediated disease.