In obese patients with coronary artery disease (CAD), the vascular endothelium is usually impaired, and the modification or reversal of endothelial dysfunction may significantly enhance treatment. Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment, but its impact on endothelial function in obese patients with CAD has not yet been investigated. Eighty consecutive obese, nonhypertensive, stable patients with CAD (65 men; mean age 65 +/- 11 years, mean body mass index 32 +/- 3 kg/m2) were randomly assigned to either sibutramine 10 mg/day (n = 40) or routine treatment (n = 40; controls) for 4 months. The percentage improvement in endothelium-dependent brachial artery flow-mediated dilation (%FMD) and endothelium-independent nitroglycerin-mediated vasodilation were assessed at baseline and after 4 months using high-resolution ultrasound. At baseline, all patients had %FMD of 5.4 +/- 3.1% and percentage improvement in endothelium-independent nitroglycerin-mediated vasodilation of 9.2 +/- 2.9%, showing no significant differences. After 4 months, however, initial body weight was reduced by 11.4 +/- 1.2% in the sibutramine group compared with only 2.2 +/- 1.3% in controls (p <0.001), demonstrating a significant improvement in postintervention %FMD (8.9 +/- 2.4%, p = 0.01, compared with baseline) in the sibutramine group compared with controls (5.2 +/- 3.6%, p = 0.68, compared with baseline). No significant therapeutic effect on the percentage improvement in endothelium-independent nitroglycerin-mediated vasodilation was seen in either group (9.2 +/- 2.5% vs 9.1 +/- 3.0%, respectively, p = 0.792). In addition, sibutramine therapy was associated with significant C-reactive protein reduction compared with routine treatment (44% vs 9%, p = 0.035). Thus, short-term therapy with sibutramine, together with diet and lifestyle intervention, is associated with improved endothelial function assessed by brachial artery %FMD in nonhypertensive, stable patients with CAD.