Cholera toxin (CT) injected ip on day 1 (day of ovulation) of the 4-day hamster estrous cycle, when circulatory progesterone is high and estrogen low, induced a massive uterine decidual reaction, a progesterone-dependent growth normally triggered by the implanting blastocyst. However, CT injected ip on day 3, when circulatory estrogen is high and progesterone low, did not induce a decidual reaction but, instead, intensified the effects of estrogen (stromal edema and stimulation of the mucosa). These cycle day effects were reproduced in one uterine horn injected intraluminally with CT, but not in the other horn of the same animal given solvent alone as a control. The intrauterine injection of CT had no effect on the concentration of serum estrogen or progesterone. The decidual reaction resulting from intrauterine injection of CT on day 1 was accompanied by increases in estrogen receptor (femtomoles per mg DNA) in both cytoplasm and nucleus. In long term ovariectomized hamsters, an ip or intrauterine injection of CT induced only histological effects of estrogen (stromal edema and mucosal mitosis) without affecting circulatory estrogen. These estrogenic effects were accompanied by increases in receptors for estrogen and progesterone in both cytoplasm and nucleus. CT injected ip into ovariectomized hamsters primed with estrogen intensified the stromal edema and mucosal mitosis and resulted in progesterone and estrogen receptor levels equal to or greater than those after the administration of CT or estrogen alone. When progesterone was included in the priming (estrogen + progesterone + CT), all receptor levels were decreased, and a massive decidual reaction resulted. Thus, the induction of estrogen receptor by CT may have been the primary event that triggered the decidual reaction. Whether CT-induced estrogen receptor is mediated by cAMP, a known mediator of CT, remains to be determined.