Parameters of cocaine self-administration behavior and vaginal cytological changes were assessed in ovariectomized rats during and after chronic self-administration. Response to novelty as measured by locomotor activity was found to correlate with cocaine self-administration on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. Chronic 17-beta estradiol (E2) replacement did not affect cocaine self-administration on FR or PR schedules of reinforcement. Acute E2 administration decreased cocaine self-administration on a PR schedule of reinforcement on the day of and on the two days following hormone treatment. Finally, the proliferation of vaginal epithelia following acute E2 was potentiated in rats both during cocaine self-administration and 30 days into withdrawal when compared with non-drug-exposed animals. These results identify response to novelty as a behavioral index predictive of cocaine self-administration liability in female rats and additionally provide evidence of psychostimulant-hormonal interactions highly relevant to female behavior and physiology.