Fluoxetine, a selective serotonin reuptake inhibitor, is currently being evaluated as a potential treatment for cocaine abuse. This 4-week inpatient study evaluated the pharmacologic interaction between fluoxetine and cocaine in healthy adult male volunteers (N = 5) with histories of cocaine abuse. Oral capsules were administered daily containing either placebo (weeks 1 and 4) or fluoxetine in a series of ascending doses (10, 20, 30, and 40 mg) where each dose was given for three to four consecutive days. Cocaine challenge sessions were conducted twice weekly, once at each active dose level and twice during both the placebo and washout phases. Subjects received three ascending intravenous doses of cocaine (0, 20, and 40 mg) 1.5 hours apart and were monitored on physiologic and subjective measures. Cocaine alone increased heart rate, blood pressure, and pupillary diameter and increased subjective reports reflecting positive mood effects and drug liking. Fluoxetine (40 mg) significantly decreased subjective ratings of cocaine's positive mood effects on several visual analog measures. Fluoxetine also attenuated the mydriatic effect of cocaine. No adverse physiologic interactions between the two drugs were observed on cardiovascular measures. These data suggest that fluoxetine may be safely used in the presence of cocaine use and should be investigated further as a potential pharmacotherapy for cocaine abuse.