Because current weight-reduction treatments have considerable recidivism, a therapy that could help patients maintain weight loss would be of benefit. A six-center, randomized, double-blind trial compared the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride, and placebo on maintenance of weight loss. Obese outpatients who had lost ≤3.6 kg after 8 weeks of single-blind fluoxetine 60 mg/day in the qualification phase (N=317 [70.4% of patients entered]; mean ± standard deviation [SD] weight loss, 6.8 ± 2.8 kg) were randomly assigned to fluoxetine 20 mg/day (N=104), fluoxetine 60 mg/day (N=106), or placebo (N=107) for 40 weeks (maintenance phase). Patients received minimal nutrition/dietary counseling. Qualification phase clinic visits were biweekly; maintenance phase visits were monthly for 4 months, then bimonthly for 6 months. Patients treated with fluoxetine 60 mg/day continued to lose weight for 8 additional weeks (16 weeks total; maximum mean ± SD weight loss, 7.2 ± 4.6 kg); those treated with fluoxetine 20 mg/day or placebo began to regain weight. Mean weights remained below baseline values at week 48 (all groups); treatment differences were not statistically significant. Study completion rates were comparable (fluoxetine 20 mg/day, 67.3%; fluoxetine 60 mg/day, 56.6%; placebo, 67.3%; p = 0.175). Among commonly reported adverse events (>10% incidence), only asthenia was reported statistically significantly (p< 0.050) more frequently with fluoxetine than with placebo. Few patients discontinued for any single adverse event. Fluoxetine 60 mg/day was effective for a longer period than fluoxetine 20 mg/day or placebo in maintaining weight loss. Overall, fluoxetine was safe and well tolerated.