Cocaine is known to exert sexually dimorphic HPA axis effects in rats and to disrupt estrous cyclicity and/or fertility in rats, nonhuman primates, and humans. The present studies investigated the reciprocal interactions between ovarian hormones and HPA axis responses to cocaine. Thirty minutes after injection, cocaine (15 mg/kg i.p.) increased serum ACTH and corticosterone more in cycling than ovariectomized females or male rats. ACTH and corticosterone were highest in proestrus when estradiol was elevated. Cocaine did not alter serum estradiol in females or testosterone in males but did stimulate progesterone secretion in both sexes. Cocaine-stimulated progesterone secretion was significantly greater in females than in males or ovariectomized females, and greater in proestrous than diestrous 1 rats. Cocaine stimulated corticosterone and progesterone secretion in sham-adrenalectomized, but not adrenalectomized rats, indicating that the adrenal gland and not the ovary is the source of cocaine-stimulated progesterone. Estrogen influenced cocaine-stimulated progesterone secretion more than corticosterone, suggesting different release mechanisms for the two steroids in the adrenal. These results suggest that adrenally derived progesterone could contribute to cocaine-induced physiological changes, including inhibited gonadotropin release.