OBJECTIVE - To evaluate the effects over 2 years of a weight loss program combining several weight loss strategies on weight loss and diabetes control in overweight subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS - A total of 59 overweight or obese individuals with type 2 diabetes were randomly assigned to either a combination therapy weight loss program for 2 years (C therapy) or a standard therapy weight loss program for 1 year followed by a combination therapy weight loss program in the 2nd year (S/C therapy). C therapy combined the use of meal replacement products, repetitive intermittent low-calorie-diet weeks, and pharmacologic therapy with sibutramine. Outcome measures included changes in weight, glycemic control, plasma lipids, blood pressure, and body composition over 2 years. RESULTS - A total of 48 participants (23 in the C therapy group and 25 in the S/C therapy group) completed 2 years of study. After 2 years, the C therapy group had weight loss of 4.6 ± 1.2 kg (P < 0.001) and a decrease in HbA1c of 0.5 ± 0.3% (P = 0.08) from baseline. At 2 years, the C therapy group had significant reductions in BMI, fat mass, lean body mass, and systolic blood pressure. The S/C therapy group showed changes in weight and HbA1c in year 2 of the study that were similar to those demonstrated by the C therapy group in year 1. CONCLUSIONS - This combination weight loss program resulted in significant weight loss and improved diabetes control over a 2-year period in overweight subjects with type 2 diabetes.