Obstructive sleep apnea syndrome (OSAS) is a commonly seen disorder characterized by repeated episodes of upper airway obstruction during sleep leading to intermittent hypoxemia or arousal. We aim to evaluate the effects of positive airway pressure (PAP) treatment on daytime sleepiness and serum Substance P (SP) levels in OSAS patients. Seventy-one consecutive patients with newly diagnosed OSAS and 19 non-apneic control subjects were enrolled to the study. PAP treatment indicated subjects were re-evaluated after 3 months of treatment. Morning SP levels of OSAS patients and Epworth sleepiness scale (ESS) were assessed at the beginning and then after 3 months of PAP treatment. Of the patients 71 (78.9%) were male and 19 (21.1%) were female, with a median age of 45 [20-62]. The levels of SP in the OSAS group were significantly lower than the snorer group and a significant correlation was not found between serum levels of SP and ESS. SP levels were negatively correlated with AHI. The baseline SP median was 336.1pg/mL [121.6-536.1], while the 3rd month SP median was 213.1pg/mL [103.5-727.6]. Serum SP values were found to have significantly decreased at 3months (p<0.0001). Statistically significant correlation was not found between percentage of ESS change and the percentage of SP change. It can be assumed that the SP level is reduced as part of the compensation mechanism in OSAS cases and supporting this mechanism, the PAP therapy further reduces the SP value by relieving the cases from apnea and the intermittent hypoxia burden.