The influence of coumestrol on the action of estradiol was examined in oral and parenteral tests. Coumestrol did not antagonize the uterotrophic action of estradiol when administered either prior to, or jointly with, E2 treatment, or when administered orally or parenterally. Additive effects on estradiol stimulation of uterine weight and reduction of cytosolic estrogen receptor binding were observed following oral, but not parenteral, administration of coumestrol. On the other hand, coumestrol pretreatment did appear to dampen estradiol's induction of progestin receptors, uterine protein, and nuclear estrogen receptor binding. However, even at those endpoints where coumestrol pretreatment did dampen estradiol action, coumestrol itself produced an estrogenic response. These findings contradict the assumption that all phytoestrogens are necessarily antiproliferative agents and argue for specific identification of the actions of each chemical.