The protective effect of progesterone or tamoxifen, an antiestrogenic agent, was investigated in estrogen-induced mammary carcinogenesis. Multiple mammary tumors (MT) of tubular or medullary carcinoma type developed at a high rate following prolonged treatment of ovariectomized W/Fu rats with diethylstilbestrol or 17 beta-estradiol. All MTs were located adjacent to the nipple and were slow-growing. The induction rate, multiplicity and size of estrogen-induced MTs were reduced by the simultaneous administration of either progesterone or tamoxifen. The estrogen-induced pituitary tumorigenesis was effectively inhibited by tamoxifen treatment, but it was not affected by progesterone. The results indicated that the inhibitory effect of progesterone or tamoxifen in estrogen-induced carcinogenesis is attributable to interference with the binding of estrogen to the estrogen receptors on the target cells.