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Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women.Cocaine-dependent women with low (< 4 ng/ml; n = 16) and high (≥ 4 ng/ml; n = 9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6 mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60 min after the cue.The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition × progesterone level interaction, F1,23 = 9.8, p = 0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition × progesterone level interaction, F1,23 = 13.9, p = 0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition.These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women.We examined the effect of endogenous progesterone on reactivity following a stressor.High-progesterone cocaine-dependent women showed attenuated subjective reactivity.Progesterone may protect against stress-induced relapse in cocaine-dependent women.