Obstructive sleep apnea syndrome (OSAS) is associated with obesity and insulin resistance. Visfatin is an insulin-mimicking adipokine, which is considered a link between obesity and insulin resistance. Aim of this study was to evaluate levels of plasma visfatin in patients with severe OSAS and examine their potential correlation with sleep characteristics and several biochemical parameters. Nondiabetic patients with severe OSAS (Apnea Hypopnea Index > 30/h, n = 32) and healthy controls (Apnea Hypopnea Index < 5/h, n = 12), examined with polysomnography, underwent a biochemical analysis to estimate fasting levels of visfatin, glucose, insulin, C-peptide, and lipid profile. The two groups were matched for age and body mass index (BMI). OSAS patients had significantly higher fasting insulin levels (p = 0.045), but no difference was shown in visfatin between patients and controls (p = 0.585). In OSAS patients, visfatin levels correlated positively with sleep latency (r = 0.539, p = 0.01) and triglyceride levels (r = 0.584, p = 0.036) and negatively with total sleep time, percentage of stage 2 and REM sleep, and LDL-cholesterol levels (r = -0.659 and p = 0.001; r = -0.496 and p = 0.019; r = -0.577 and p = 0.005; r = -0.804 and p = 0.003, respectively). No association was found, however, between visfatin levels and HOMA index or indices of nocturnal hypoxia. In patients with severe OSAS, visfatin levels are associated with characteristics of sleep architecture. However, there is no correlation between visfatin and insulin resistance or nocturnal hypoxia.