OBJECTIVES: Rimonabant, the first selective CB-1 receptor blocker, has proven effective in improving cardiometabolic risk factors and reducing weight in overweight and obese individuals. This study evaluated its cost-effectiveness in patients with a BMI>27 kg/m2 in the UK. METHODS: A discrete event simulation was created to take into account multiple time-dependent risk factors – it predicts changes in anthropomorphic and physiologic parameters based on analysis of pooled RIO trials data, while simultaneously predicting onset of diabetes, cardiovascular events and diabetic complications. After 100,000 individuals are assigned baseline characteristics by sampling UK data, their baseline risks are predicted and they enter a main module where these are applied. Periodic updating takes place at doctors' visits and other events, such as premature treatment discontinuation and complications. Resource use, costs and utilities were obtained from UK databases. All outcomes are discounted at 3.5%/year. RESULTS: After one year treatment, patients on rimonabant plus diet and exercise lose more than three times the weight and show greater improvements in other cardiometabolic risk factors than patients on diet and exercise alone. With diet and exercise, 633 cardiovascular and 411 microvascular events are predicted to occur per 1000 patients, over 60 years. Lifetime costs average £5692/patient. One year of rimonabant reduces cardiovascular and microvascular events by 18 and 10, respectively, with a corresponding reduction in complication costs. Discounted life expectancy increases by 40.2 years, and QALYs by 113.8. Extending treatment to 5 years increases life years and QALYs gained by a further 38 and 48%, respectively. Extensive sensitivity analyses, including varying the cost of treatment with rimonabant, indicate that rimonabant is cost-effective over a wide range of inputs. CONCLUSION: Rimonabant for the treatment of overweight or obese patients with or without comorbidities in the UK should be associated with acceptable cost-effectiveness ratios under a wide range of assumptions.