© 2016, Society of General Internal Medicine. Background: Weight gain and other metabolic sequelae of antipsychotic medications can lead to medication non-adherence, reduced quality of life, increased costs, and premature mortality. Of the approaches to address this, behavioral interventions are less invasive, cost less, and can result in sustained long-term benefits. Objective: We investigated behavioral weight management interventions for veterans with mental illness across four medical centers within the Veterans Affairs (VA) Healthcare System. Design: We conducted a 12-month, multi-site extension of our previous randomized, controlled study, comparing treatment and control groups. Participants: Veterans (and some non-veteran women) diagnosed with mental illness, overweight (defined as having a BMI over 25), and required ongoing antipsychotic therapy. Interventions: One group received “Lifestyle Balance” (LB; modified from the Diabetes Prevention Program) consisting of classes and individual nutritional counseling with a dietitian. A second group received less intensive “Usual Care” (UC) consisting of weight monitoring and provision of self-help. Main Measures: Participants completed anthropometric and nutrition assessments weekly for 8 weeks, then monthly. Psychiatric, behavioral, and physical assessments were conducted at baseline and months 2, 6, and 12. Metabolic and lipid laboratory tests were performed quarterly. Key Results: Participants in both groups lost weight. LB participants had a greater decrease in average waist circumference [F(1,1244) = 11.9, p < 0.001] and percent body fat [F(1,1121) = 4.3, p = 0.038]. Controlling for gender yielded statistically significant changes between groups in BMI [F(1,1246) = 13.9, p < 0.001]. Waist circumference and percent body fat decreased for LB women [F(1,1243) = 22.5, p < 0.001 and F(1,1221) = 4.8, p = 0.029, respectively]. The majority of LB participants kept food and activity journals (92%), and average daily calorie intake decreased from 2055 to 1650 during the study (p < 0.001). Conclusions: Behavioral interventions specifically designed for individuals with mental illness can be effective for weight loss and improve dietary behaviors. “Lifestyle Balance” integrates well with VA healthcare’s patient-centered “Whole Health” approach. ClinicalTrials.gov identifier NCT01052714.