Background Cardiovascular risk factors associated with obesity, including dyslipidemia, can be improved by weight loss. The main dyslipidemia associated with obesity is elevated serum triglyceride and decreased serum high-density lipoprotein cholesterol (HDL-C) levels. Methods A total of 322 obese patients (body mass index ≥27) with serum triglyceride levels ≥250 mg/dL and ≤1000 mg/dL and serum HDL-C levels ≤45 mg/dL (women) and ≤40 mg/dL (men) were placed on a step I American Heart Association diet and subsequently randomized to sibutramine 20 mg (n = 162) or placebo (n = 160) once daily for 24 weeks. Results Patients taking sibutramine had significantly greater mean weight loss than those receiving placebo (–4.9 kg vs –0.6 kg, P ≤.05). Forty-two percent of the sibutramine group lost ≥5% of baseline weight and 12% lost ≥10% compared with 8% and 3%, respectively, of the placebo group (P ≤.05). Mean decreases in serum triglyceride levels among 5% and 10% weight-loss responders in the sibutramine group were 33.4 mg/dL and 72.3 mg/dL, respectively, compared with an increase of 31.7 mg/dL among all patients receiving placebo (P ≤.05). Mean increases in serum HDL-C levels for 5% and 10% weight-loss responders in the sibutramine group were 4.9 mg/dL and 6.7 mg/dL, respectively, compared with an increase of 1.7 mg/dL among all patients in the placebo group (P ≤.05). Adverse events and discontinuation rates were similar in the sibutramine and placebo groups, although sibutramine-treated patients had mean increases in systolic and diastolic blood pressure of 2 to 3 mm Hg relative to placebo. Conclusions In overweight and obese patients with high serum triglyceride levels and low serum HDL-C levels, treatment with sibutramine was associated with significant improvements in body weight and in serum triglyceride and HDL-C levels. (Am Heart J 2001;142:489-97.)