Estrogen rapidly enhances dopamine (DA) activity in the striatum and nucleus accumbens as well as behavioral responses to psychomotor stimulants in female rats but not males. This experiment was conducted to investigate the role of pulsatile estrogen treatment on and sex differences in the development and expression of sensitization of cocaine-induced rotational behavior in rats with unilateral striatal DA denervation. Four groups were tested: ovariectomized (OVX) females treated with 5 microg of estradiol benzoate (OVX+E), OVX females, castrated (CAST) males, and intact males. Animals received estrogen or vehicle 30 min before cocaine (0, 5, 10, or 20 mg/kg, i.p.) on 4 consecutive days, followed by 3 d without treatment for 3 weeks. At the conclusion of the experiment, animals were withdrawn from hormone and/or cocaine for 10 d, and all groups underwent a challenge test with 10 mg/kg cocaine. We report here that OVX+E females exhibit significantly greater sensitization of rotational behavior with a faster rate of sensitization than the three other groups. There is also a sex difference independent of gonadal hormones: OVX females exhibit a greater magnitude of sensitization of rotational behavior than do CAST males at 20 mg/kg cocaine. Furthermore, on the challenge test, OVX+E animals tested without estrogen treatment continue to exhibit greater rotational behavior than do all other groups. Thus, estrogen enhances sensitization to cocaine, there are sex differences in behavioral sensitization, and sensitization that develops under conditions with estrogen persists even when estrogen levels are low.