OBJECTIVES: Obesity is a major risk factor for type 2 diabetes, cardiovascular disease and stroke. Moderate weight loss of 5–10% is proven to be beneficial, but often difficult to achieve with diet/exercise alone. The addition of sibutramine can reduce and maintain weight loss through increased satiety and enhanced resting metabolic rate. This study reviews the safety, efficacy and cost-effectiveness of sibutramine with diet/exercise in obese patients. METHODS: A patient level analysis was conducted of 23 RCTs of sibutramine with diet/exercise compared with diet/exercise alone. Dichotomous outcomes (proportion of patients losing ≥ 5% body weight) and multivariate risk factor-adjusted continuous means (BMI, SBP/DBP, HbA1c and lipids) were calculated. Least squares regression models were developed to determine the relationship between BMI change and cardiovascular risk factors used in the economic model. A Markov decision-analytic model using the Monte-Carlo simulation was employed to examine cost-effectiveness. Hypothetical patients were subject to risk of type 2 diabetes, CVD and stroke. Diabetic patients were at added risk of amputation, blindness and renal failure. Simulation of events was performed using the Framingham Heart Study and the UK Prospective Diabetes Study. RESULTS: Significant clinical benefits were demonstrated with sibutramine and diet/exercise compared with diet/exercise alone: proportion of patients achieving ≥ 5% weight loss (51.6 vs 22.3% respectively; p <0.0001), BMI (–1.65 [–1.97, –1.34] kg/m2; p <0.0005), absolute weight (–3.84 [–5.18, –2.49] kg; p <0.0005), HDL (4.07 [1.50, 6.65] mmol/L; p = 0.002) and triglycerides (–12.17 [–21.82, –2.52]; p = 0.013). Small increases in blood pressure (1–3 mmHg) and heart rate (4–5 beats/minute) were observed. Sibutramine was a cost-effective addition to diet/exercise (approximately AUD$40,000 per additional QALY). Sensitivity analyses demonstrated the model to be robust. CONCLUSIONS: Sibutramine is a safe, effective, and cost-effective intervention in the prevention of obesity-related complications through weight loss and weight maintenance.