OBJECTIVE - The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS - Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10-15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year. RESULTS - At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (-7.3 ± 1.3 kg vs. -0.8 ± 0.9 kg, P < 0.001) and reduction in HbA1c (-0.6 ± 0.3 vs. 0.0 ± 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA1c (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups. CONCLUSIONS - This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.