This study was designed to investigate if the kappa opioid system regulates the locomotor response to cocaine in the female rat and to determine if the effect is dependent on estradiol treatment. Adult rats were ovariectomized (OVX) and half received an estradiol (OVX-EB) implant. After a week, rats were injected for 5 consecutive days with vehicle or with the KOPr agonist U-69593 (0.16 mg/ kg, 0.32 mg/kg, 0.64 mg/kg) 15 min prior to cocaine injection (15 mg/kg). Following a 7 day drug free period, rats were challenged with cocaine (Day 13). The locomotor response to cocaine was measured on days 1, 5 and 13. U-69593 (0.32 mg/kg) decreased cocaine-induced locomotor activity in drug naïve OVX and OVX-EB rats. These results indicate that the acute effects of U-69593 are independent of estradiol treatment. Repeated exposure to U-69593 (0.32 mg/kg) prior to cocaine decreased the development of behavioral sensitization in OVX-EB rats. This decrease in cocaine-induced hyperlocomotion persisted after one week of cocaine withdrawal. These data indicate that the KOPr system participates in estradiol modulation of cocaine-induced behavioral sensitization in the female rat.