We investigated the effects of high doses of estrogen on the basal and stimulated secretion of PRL. Daily administration of 0.1 micrograms estradiol benzoate to female mice for 4 weeks significantly increased the amplitude of PRL release induced by perphenazine. A dose of 1.0 micrograms had no stimulatory effect, while doses of 10, 20, and 50 micrograms completely prevented the release of PRL in response to perphenazine. The rise in basal serum PRL concentrations seen at lower doses of estradiol benzoate was also minimized with 20- and 50-micrigrams doses. At the same time, PRL concentrations within the pituitary gland as well as pituitary weight consistently increased in response to all high doses of estradiol benzoate tested, although the increment at the highest dose (50 micrograms) was somewhat smaller. These results suggest that prolonged administration of estrogen in large amounts may be detrimental to the natural, acute release of PRL. We postulate that this effect may account, in part, for the observed mammostatic and antigalactic effects of high doses of estrogen.