CONTEXT: The prevalence of overweight and obesity in the United States remains high. Commercial weight loss programs may contribute to efforts to reduce the prevalence of overweight and obesity, although few studies have examined their efficacy in controlled trials. OBJECTIVE: To test whether a free prepared meal and incentivized structured weight loss program promotes greater weight loss and weight loss maintenance at 2 years compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial of weight loss and weight loss maintenance in 442 overweight or obese women (body mass index, 25-40) aged 18 to 69 years (mean age, 44 years) conducted at US institutions over 2 years with follow-up between November 2007 and April 2010. INTERVENTION: The program, which involves in-person center-based or telephone-based one-to-one weight loss counseling, was available over a 2-year period. Behavioral goals were an energy-reduced, nutritionally adequate diet, facilitated by the inclusion of prepackaged food items in a planned menu during the initial weight loss phase, and increased physical activity. Participants assigned to usual care received 2 individualized weight loss counseling sessions with a dietetics professional and monthly contacts. MAIN OUTCOME MEASURES: Weight loss and weight loss maintenance. RESULTS: Weight data were available at 24 months for 407 women (92.1% of the study sample). In an intent-to-treat analysis with baseline value substitution, mean weight loss was 7.4 kg (95% confidence interval [CI], 6.1-8.7 kg) or 7.9% (95% CI, 6.5%-9.3%) of initial weight at 24 months for the center-based group, 6.2 kg (95% CI, 4.9-7.6 kg) or 6.8% (95% CI, 5.2%-8.4%) for the telephone-based group, and 2.0 kg (95% CI, 0.6-3.3 kg) or 2.1% (95% CI, 0.7%-3.5%) for the usual care control group after 24 months (P < .001 for intervention effect). CONCLUSION: Compared with usual care, this structured weight loss program resulted in greater weight loss over 2 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00640900.