The aim of this study was to compare the efficacy of topiramate versus a placebo in the treatment of adiposity in women undergoing olanzapine therapy. We also assessed changes health-related quality of life, the patient's actual state of health, and psychologic impairments. The 10-week, random, double-blind, placebo-controlled study included 43 women who had been treated with olanzapine (mean dose 7.8 +/- 3.6 in the topiramate group and 7.2 +/- 3.1 in the placebo group) and had gained weight as a side effect. The subjects were randomly assigned to topiramate (n = 25) or a placebo (n = 18). Primary outcome measures were weight checks and self-reported changes on the scales of the SF-36 Health Survey, Bf-S Scale of Well-Being, and the Adjective Checklist EWL-60-S. Weight loss was observed and was significantly more pronounced in the topiramate-treated group (difference in weight loss between the 2 groups: 5.6 kg, 95% CI = -8.5, -3.0, P < 0.001). In comparison with the placebo group, significant changes on 7 (7/8) scales of SF-36 Health Survey (all P < 0.001), on all 6 scales of the EWL-60-S, and on the Bf-S were observed in the topiramate-treated subjects after 10 weeks. All patients tolerated topiramate well. Topiramate appears to be a safe and effective agent in the treatment of weight gain that occurred during olanzapine treatment. Significantly positive changes in health-related quality of life, the patient's actual state of health, and psychologic impairments were observed.