Objective: To demonstrate the effectiveness of a Diabetes Prevention Programinspired 12-month behavioral intervention for patients with severe mental illness (SMI) and medicationassociated obesity. Method: This randomized, controlled, parallel, superiority study screened 225 volunteers from November 2005 to August 2008 at the VA Greater Los Angeles Healthcare System. 122 outpatients with DSM-IVdiagnosed SMI taking antipsychotic medications who had ≥ 7% weight gain or body mass index (BMI) > 25 were randomized by computer-generated number to Lifestyle Balance treatment intervention (n = 60) or usual care control (n = 62) groups. Clinical raters were masked to randomization. Treatment intervention included weekly classes and individual counseling for 8 weeks, food and exercise diaries, rewards, caregiver consultations, and monthly booster classes and counseling for 1 year. Controls received self-help materials and visited at equivalent intervals without formal classes or counseling. Outcomes were changes in anthropometric measurements, psychiatric symptoms, health knowledge, and glucose, hemoglobin A1c, and lipid levels. Results: Our intention-to-treat analysis found significant differences in predicted trajectory of mean weight change between the groups over 12 months (P < .01), with treatment participants expected to lose an average 4.6 kg, while control participants would gain an average 0.6 kg. BMI and body fat percentage followed the same pattern. Both groups demonstrated statistically significant improvements in health knowledge quiz scores over time (P = .006), without significant difference between groups. Conclusions: Treatment was more effective than usual care control in treating medication-associated obesity, independent of SMI diagnosis, antipsychotic medication, and knowledge gained, suggesting that behavioral interventions are effective in SMI patients.