Excessive daytime sleepiness (EDS) is one of the most frequent symptoms in patients with obstructive sleep apnea syndrome (OSAS). However, not all patients with OSAS manifest EDS. The aim of this study was to assess whether differential circulatory levels of inflammatory mediators would account for differences in somnolence among patients with OSAS. Patients were prospectively recruited from referral patient cohort to the university hospital sleep center. A total of 50 consecutive patients with OSAS undergoing overnight polysomnography with or without EDS and 20 controls were evaluated. EDS was assessed using the Epworth sleepiness scale (ESS) and the multiple sleep latency test after overnight polysomnography. EDS was defined when the ESS was >10 and the mean sleep latency <10 min. Fasting blood was drawn in the morning after polysomnography. Circulating levels of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), 8-isoprostaglandin F2alpha (8-iso-PGF2alpha), and P-selectin were measured with commercially available high sensitivity kits. Although patients with OSAS have elevated levels of ICAM-1, IL-6, and TNFalpha, there were no statistically significant differences in any of the inflammatory mediators between patients with EDS and without EDS. Emergence of EDS in the context of OSA does not appear to result from the selective increase of any particular somnogenic substance, i.e., TNFalpha, IL-6, ICAM-1, 8-iso-PGF2alpha, and P-selectin in the context of sleep-disordered breathing.