In this report we examined the effect of tamoxifen upon the nigrostriatal dopaminergic system. Ovariectomized mice were subjected to one of the following treatments: two subcutaneous injections administered on successive days of the sesame oil vehicle (control), estradiol benzoate (EB-10 micrograms), tamoxifen citrate (TMX 125 micrograms) or a combination of EB+TMX. At 24 h after the second injection, the caudate nucleus was superfused in vitro to evaluate the effects of these treatments upon basal as well as potassium stimulated (30 mM) dopamine release rates. In addition, uteri were weighed from each animal. Basal and total fractional dopamine release rates from the caudate nucleus of control mice were significantly lower than those of the other three treatments, which failed to differ among each other. Potassium minus (-) basal stimulated dopamine release rates failed to differ significantly among the four treatment conditions. Uterine weights of the TMX treated mice were significantly greater than controls, but significantly lower than EB and EB+TMX animals. These data show that TMX can significantly increase caudate nucleus dopamine release to levels observed in EB treated mice. These agonistic effects of TMX upon nigrostriatal dopaminergic function can be contrasted with its relatively weak estrogenic effects upon uterine weights and indicate the discriminatory, system specific effects that can be exerted by this anti-estrogen. This demonstration of TMX's ability to modulate central nervous system function is of particular relevance in light of pending clinical trials for the prophylactic use of TMX in the treatment of women for breast cancer.