Women initiate cocaine use at a younger age and have more complications (e.g., higher rates of major or minor depression) related to cocaine use than men. It has been proposed that estrogens play an important role in these sex differences. The addictive potential of psychoactive drugs can be measured in rats via a rewarding intracranial self-stimulation (ICSS) procedure. The rate-independent method of ICSS allows researchers to assess the "pure" rewarding effect of cocaine without influence of nonspecific motor reactions. The present study aimed to estimate effects of estradiol and a combination of estradiol and cocaine on ICSS in ovariectomized female rats. 17-β-estradiol (5μg/animal/day, 2 days) produced a long-lasting gradual lowering of the thresholds for ICSS. The ability of estradiol to decrease thresholds for ICSS has never been shown previously. Combination of 17-β-estradiol and cocaine (5.0mg/kg, 5 days) produced a greater effect on ICSS thresholds than the effect of either compound alone. No tolerance or sensitization to cocaine developed during the study. Present findings suggest estradiol increases sensitivity of the brain reward system in rats, which may have an important implication in understanding sex differences in cocaine effects.