Background: Lifestyle changes involving diet, behavior, and physical activity are the cornerstone of successful weight control. Incorporating meal replacements (1-2 per day) into traditional lifestyle interventions may offer an additional strategy for overweight patients in the primary care setting. Methods: One hundred thirteen overweight premenopausal women (mean±SD age, 40.4±5.5 years; weight, 82±10 kg; and body mass index, 30±3 kg/m2) participated in a 1-year weight-reduction study consisting of 26 sessions. The women were randomly assigned to 3 different traditional lifestyle-based groups: (1) dietitian-led group intervention (1 hour per session), (2) dietitian-led group intervention incorporating meal replacements (1 hour per session), or (3) primary care office intervention incorporating meal replacements with individual physician and nurse visits (10-15 minutes per visit). Results: For the 74 subjects (65%) completing 1 year, the primary care office intervention using meal replacements was as effective as the traditional dietitian-led group intervention not using meal replacements (mean±SD weight loss, 4.3%±6.5% vs 4.1%±6.4%, respectively). Comparison of the dietitian-led groups showed that women using meal replacements maintained a significantly greater weight loss (9.1%±8.9% vs 4.1%±6.4%) (P=.03). Analysis across groups showed that weight loss of 5% to 10% was associated with significant (P = .01) reduction in percentage of body fat, body mass index, waist circumference, resting energy expenditure, insulin level, total cholesterol level, and low-density lipoprotein cholesterol level. Weight loss of 10% or greater was associated with additional significant (P = .05) improvements in blood pressure and triglyceride level. Conclusions: A traditional lifestyle intervention using meal replacements can be effective for weight control and reduction in risk of chronic disease in the physician's office setting as well as in the dietitian-led group setting.