Steroid hormones may influence the clinical expression of immunologic disease; however, their mechanism of action is uncertain. By using an experimental model, we studied the effect of sex steroids on the clearance of antibody-coated cells by macrophages in the spleen and liver. Progesterone significantly inhibited the clearance of IgG-coated E by splenic macrophages, whereas no effect was observed on the clearance of heat-altered E. This effect of progesterone was observed at serum concentrations which are attained during human pregnancy and the menstrual cycle. Furthermore, when splenic macrophages were isolated from progesterone-treated animals, they expressed decreased Fc gamma R activity. In addition, structural analogs of progesterone which have diminished glucocorticoid and progesterone activity retained this effect on macrophage Fc gamma R. In contrast, the estrogens estradiol and estriol as well as a structural estrogen analog with minimal estrogenic activity, 1,3,5(10)-estratrien-3,16 beta-diol, enhanced splenic macrophage Fc gamma R-dependent clearance. This action of estradiol could be partially inhibited by the antiestrogen tamoxifen. However, estradiol did not affect the C3-dependent clearance of IgM-coated E by hepatic macrophages. Concurrent administration of estradiol and progesterone demonstrated that the action of estradiol was predominant. These studies indicate that sex steroids alter splenic macrophage Fc gamma R function in vivo. This result may explain the alteration of disease activity in some human immunologic disorders during changes in hormonal state. Furthermore, analogs of progesterone and estrogen, as well as antiestrogens, which minimally affect the sex organs, retain the ability to alter splenic macrophage Fc gamma R function.