The effects of female sex hormones on responses to cocaine have not been systematically investigated in women. In this study, the safety and efficacy of acute progesterone treatment on smoked cocaine response was examined in female cocaine users. Five women had two experimental sessions during the early follicular phase, within 3-9 days after the beginning of their menses. In each experimental session, subjects received a single 200-mg dose of progesterone or placebo orally. Starting 2 h after the medication treatment, subjects received three deliveries of 0.4-mg/kg smoked cocaine 30 min apart. Progesterone treatment, compared to placebo, did not affect the blood pressure and heart rate changes in response to cocaine deliveries. For subjective responses to cocaine, the average of five-item Cocaine Effects Questionnaire (CEQ) was attenuated under progesterone treatment compared to placebo. For individual items of CEQ, progesterone treatment was associated with diminished rating of "feel the effect of last dose" in response to cocaine. These preliminary results suggest that acute progesterone treatment, given during the early follicular phase, may attenuate some of the subjective effects of cocaine. Further studies are warranted to examine the effects of progesterone treatment on cocaine dependence.