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Although the disproportionate frequency of several immunologic disorders among women is well recognized, the effect of sex steroids on immunologic processes is unclear. We used an animal model, which has helped to elucidate the effect of corticosteroids in vivo, to quantitatively assess the effect of estradiol and steroid analogues on the immune clearance of IgG-coated erythrocytes. While corticosteroids impaired the clearance of IgG-coated erythrocytes, estradiol, in doses comparable to those achieved during pregnancy, significantly enhanced the clearance. Estradiol, however, did not enhance the splenic clearance of heat-altered erythrocytes. Splenic macrophages isolated from estradiol-treated animals expressed enhanced receptor affinity for the Fc portion of immunoglobulin G [Fc(IgG)], an effect probably responsible for the enhanced in vivo clearance. No consistent effect of estradiol on the splenic macrophage C3 receptors was observed. The synthetic androgen danazol, the mineralocorticoid deoxycorticosterone, and the cortisol metabolite tetrahydrocortisone did not alter the clearance of IgG-coated cells after 7 d of therapy. The estrogen antagonist/agonist tamoxifen enhanced the clearance of IgG-coated cells, but to a lesser extent than estradiol. An effect of estrogens on macrophage Fc (IgG) receptor-mediated clearance may explain in part the variation in clinical expression of several autoimmune disorders during changes in hormonal state, such as pregnancy.