Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.