Obesity is the major confounding factor in the relationship between obstructive sleep apnea and increased risk for cardiovascular disease. The aim of the study was to investigate the association of sleep apnea severity with insulin resistance, leptin, and CRP levels in a cohort of male patients. Sixty-seven men referred to our sleep laboratory for evaluation of suspected obstructive sleep apnea syndrome (OSAS) were divided into three groups according to apnea severity: non-OSAS group (n=15), mild to moderate OSAS group (n=26), and severe OSAS (n=26). Insulin resistance was estimated by the homeostasis model assessment method. HOMA values were similar in the three groups: (3.2+/-2.2 vs. 3.3+/-1.8 vs. 3.6+/-1.5, respectively, p=0.71). Leptin levels were higher in the mild to moderate OSAS group (23.1+/-21.8 ng/ml, p<0.05) and in the severe OSAS group (20.2+/-17.5 ng/ml, p<0.05) than in the non-OSAS group (9.4+/-6.4 ng/ml). CRP levels were significantly higher in severe sleep apnea (0.35+/-0.3 vs. 0.19+/-0.1 mg/dl, p<0.05). In multiple regression analyses, waist-to-hip ratio (WHR) was the most significant determinant of HOMA estimation for insulin resistance. WHR and the percentage of total sleep time spent with hypoxemia (%TST with SaO2 <90%) were significant predictors for leptin levels, while body mass index (BMI) and the %TST with SaO2 <90% were the best predicting parameters for CRP levels. Insulin resistance estimated by the HOMA method in male patients with OSAS was not associated with sleep apnea severity independent of obesity. The severity of nocturnal hypoxemia was associated with leptin and CRP levels independent of obesity.