Preclinical data suggest a link between stress reactivity and cocaine self-administration by rodents. Serotonin appears to modulate the hypothalamic-pituitary-adrenal (HPA) axis. We studied the effects of chronic treatment with the serotonin reuptake inhibitor fluoxetine 40 mg/day on subjective and hormonal responses to cocaine cues in 22 subjects participating in a controlled clinical trial for cocaine dependence. Fluoxetine antagonized the cue-induced increase in cortisol but increased subjects' ratings of the likelihood of cocaine use in response to cocaine cues. Cortisol response to cocaine cues was not related to subjective craving. Activation of the HPA axis by cocaine cues does not appear to be a necessary mediator of cue-induced craving.