Background: Although obstructive sleep apnea (OSA) is strongly linked with obesity, both conditions have been associated with increased cardiovascular risk including glucose intolerance, dyslipidemia, and hypertension independent of one another. Weight loss is known to improve both cardiovascular risk and OSA severity. The aim of this study was to evaluate cardiovascular and metabolic changes, including compartment-specific fat loss in obese OSA subjects undergoing a weight loss program. Design: Observational study. Participants: 93 men with moderate-severe OSA. Interventions: 6-month open-label weight loss trial combining sibutramine (a serotonin and noradrenaline reuptake inhibitor) with a 600-kcal deficit diet and exercise. Measurements and Results: At baseline and following 6 months of weight loss, OSA was assessed together with CT-quantified intra-abdominal and liver fat and markers of metabolic and cardiovascular function. At 6 months, weight loss and improvements in OSA were accompanied by improved insulin resistance (HOMA), increased HDL cholesterol, and reduced total cholesterol/HDL ratio. There were also reductions in measures of visceral and subcutaneous abdominal fat and liver fat. Reductions in liver fat and sleep time spent below 90% oxyhemoglobin saturation partly explained the improvement in HOMA (R2 = 0.18). In contrast, arterial stiffness (aortic augmentation index), heart rate, blood pressure, and total cholesterol did not change. Conclusions: Weight loss with sibutramine was associated with improvements in metabolic and body composition risk factors but not blood pressure or arterial stiffness. Improved insulin resistance was partly associated with reductions in liver fat and hypoxemia associated with sleep apnea.