Evidence suggests that sex differences in response to cocaine administration may be regulated by activation of progesterone and estrogen receptors. To test this hypothesis, rats were pretreated with either RU 486 (progesterone antagonist; 0, 3, or 25 mg/kg), tamoxifen (estrogen antagonist; 0, 1, or 3 mg/kg), or vehicle followed by saline or cocaine administration (15 mg/kg). Although RU 486 did not affect cocaine-induced locomotor activity in female rats, it dose-dependently decreased such activity in males (3 mg/kg significantly attenuated locomotor responses in cocaine-treated rats as compared with vehicle treatment or 25 mg/kg of RU 486). RU 486 also affected baseline serum levels of corticosterone. Males treated with 3 mg/kg of RU 486 plus cocaine had higher progesterone and corticosterone serum levels than vehicle-treated groups. In females, both doses (3 and 25 mg/kg) of RU 486 significantly attenuated corticosterone serum levels compared with vehicle treatment. For both sexes overall, tamoxifen neither significantly influenced cocaine-induced ambulatory and rearing responses nor altered cocaine-induced progesterone and corticosterone serum levels. Taken together, our results suggest that progesterone receptors have a sexually dimorphic role in cocaine-induced effects, but estrogen receptors have only a limited role. Moreover, both receptor antagonists modulate neurochemical responses differentially.