Progesterone decreases cocaine self-administration in women and in female rats. In a previous study using rats selectively bred for high (HiS) or low (LoS) saccharin intake, HiS rats escalated their cocaine intake compared with LoS rats. Our goal was to examine the effects of progesterone on the escalation of cocaine self-administration in HiS and LoS rats. Four groups of female rats were compared: HiS P (progesterone treated), LoS P, HiS VEH (vehicle treated), and LoS VEH. Rats were trained to self-administer 0.8 mg/kg cocaine intravenously under a fixed-ratio 1 schedule during daily short-access (ShA) 2-h sessions. Rats then self-administered three randomly-presented doses of cocaine (0.2, 0.4, and 1.6 mg/kg), and then had daily 6-h long-access (LgA) sessions with 0.4 mg/kg of cocaine for 21 days. Cocaine intake was then reassessed with the four doses under the ShA condition. Throughout the experiment, rats were treated with daily subcutaneous injections of progesterone (0.5 mg/kg) or an equal volume of vehicle 30 min before each session. During the initial ShA condition, HiS rats earned more cocaine infusions than LoS rats at all doses, and during the subsequent LgA condition, HiS rats escalated cocaine intake, whereas the LoS rats maintained a steady rate. Progesterone treatment potentiated escalation of cocaine intake in the HiS rats but had an opposite effect on LoS rats, attenuating their cocaine self-administration. Results from the post-LgA dose-response ShA condition indicated that both LoS and HiS vehicle-treated and progesterone-treated rats earned more infusions than pre-LgA, but mainly at low doses. These results suggest that genetic differences in drug abuse vulnerability contribute differentially to treatment outcomes during escalation, a critical phase of the drug abuse process.