Macrophage Fc receptors (FcRs) play an important role in the host defense against infection and in the pathophysiology of immune cytopenias. Modulation of macrophage FcR expression is a potential therapeutic approach to immune disorders. Glucocorticoids and progesterones decrease macrophage FcR expression. We assessed the effect of treatment with androgens and antiandrogens on the expression of macrophage FcRs using an experimental guinea pig model. Four androgens (testosterone, dihydrotestosterone, mesterolone, and danazol) and five antiandrogens (flutamide, nilutamide, cyproterone acetate, spironolactone, and finasteride) were studied. Following in vivo treatment of guinea pigs, we determined the clearance of immunoglobulin G (IgG)-sensitized erythrocytes in vivo, the binding of IgG-sensitized erythrocytes by isolated splenic macrophages, and splenic macrophage FcR cell surface expression. All of the androgens impaired the clearance of IgG-sensitized erythrocytes by decreasing splenic macrophage FcR expression. Dihydrotestosterone and mesterolone were more effective than testosterone or dihydrotestosterone. Flow cytometry and fluorescence microscopy with monoclonal antibodies demonstrated that the androgens decreased the cell surface expression of FcR1,2 more than that of FcR2. Antiandrogens did not significantly alter macrophage FcR expression. Nevertheless, antiandrogens counteracted the effects of androgens on macrophage FcR expression. These data indicate that androgens impair the clearance of IgG-coated cells by decreasing splenic macrophage FcR expression. Thus, androgens other than danazol are candidate drugs for the treatment of immune disorders.