Low levels of bilirubin are associated with an increased risk of cardiovascular adverse events. Weight reduction is known to reduce several cardiovascular risk factors, but effects on bilirubin levels have not been reported. We studied the response of weight loss therapy with sibutramine and lifestyle change on levels of total bilirubin in an overweight or obese, cardiovascular high-risk population. Data from the first 4 weeks of the lead-in period of the Sibutramine Cardiovascular Outcome study were analyzed. A total of 10 198 patients provided body weight measurements before and after 4 weeks of sibutramine treatment (10 mg daily), of whom 1059 (10.4%) gained weight, 1467 (13.7%) lost greater than 0% to 1%, 2492 (23.2%) lost greater than 1% to 2%, 2280 (21.2%) lost greater than 2% to 3%, 1498 (13.9%) lost greater than 3% to 4%, and 1402 (13.1%) lost greater than 4% of their initial weight, respectively. At screening, bilirubin concentrations were similar between weight loss groups (around 11 micromol/L, P = .7) and increased linearly as a function of weight loss. The effect was significantly more pronounced in men compared with women (P for interaction = .003). Adjusted for multiple variables, each 1% increase in weight loss was associated with 0.21-micromol/L (+/- standard error 0.027) increase in men (P < .0001) and 0.11-micromol/L (+/-0.024) increase in women (P < .0001). Short-term weight loss during administration of sibutramine in combination with diet and exercise advice is effective in increasing bilirubin levels within the reference range, with bilirubin increasing as a linear function of weight change. The effect is greater in men than in women.