Inhibitors of serotonin (5HT) re-uptake have generally been successful in inducing modest but statistically significant weight reductions in clinical trials. Citalopram is a new, highly selective inhibitor of 5HT re-uptake. It is effective and safe in relieving major depression at doses up to 60 mg daily. In our study, 72 severely obese subjects (BMI > 44 kg/m2) were instructed in a 4500 kJ carbohydrate-rich (50%) diet. The initial two week run-in diet+placebo period was followed by a 12 week double-blind period of diet+citalopram or placebo. There were seven withdrawals during the initial two weeks. Of the remaining 65 patients, 45 were randomized to 60 mg citalopram daily and 20 received placebo. A trend towards a higher frequency of nausea at week 6 was noted in the citalopram group. Weight loss during the initial two weeks was 2.01 kg. In the following 12 weeks, mean weight loss was 3.78 kg in the citalopram group vs. 2.64 kg in the placebo group (P = 0.29), reductions occurring almost entirely during the initial four weeks of the treatment period. We conclude that citalopram is of no clinical value in the treatment of obesity when added to a 4500 kJ diet.