Fluoxetine hydrochloride (Lovan, Eli Lilly and Company, Indianapolis, Indiana, USA), a specific serotonin uptake inhibitor, was compared with placebo in 458 obese outpatients in a 52-week double-blind randomized ten-site trial to study its effect on weight reduction. Patients in the fluoxetine and placebo groups were predominantly Caucasian (81% and 85%, respectively) and female (81% and 79%, respectively), with a mean body mass index (BMI) of 36.2 and 35.8 kg/m2, respectively, and a mean age of 43 years (both groups). Fluoxetine therapy (60 mg/day) resulted in statistically significantly (P < or = 0.05) greater mean weight loss than placebo to week 28. Although some patients continued to lose weight throughout the 52-week therapy period, maximum mean weight loss occurred at week 20. There was no treatment difference at 52 weeks. The change in visit frequency (biweekly to week 8, monthly to week 20, then bimonthly to week 52) may have affected results. Patients with higher baseline BMIs (> 40 kg/m2) attained and maintained a greater weight loss than patients with lower baseline BMIs (< 40 kg/m2). Two sites demonstrated greater efficacy than the study as a whole. The use of nutrition counselling at one site and behaviour modification at the other, or other site-to-site differences, may account for the improved efficacy. Fluoxetine was well tolerated and appeared to be safe therapy for the treatment of obesity with efficacy demonstrated for 28 weeks.