The etiology of the obesity-hypoventilation syndrome (OHS) is unknown. Recent reports that treatment of obstructive sleep apnea with nasal continuous positive-airway pressure eliminates the manifestations of OHS suggests that obstructive sleep apnea may contribute to OHS. The purpose of this study was to determine whether hypoxemia during sleep was more severe in patients with OHS than in those without OHS. In our sleep laboratory, we studied 32 subjects with a ratio of the forced expiratory volume in one second over the forced vital capacity (FEV1/FVC) greater than 0.73 and no neuromuscular disease. Seven subjects had OHS characterized by obesity and daytime hypercapnia, and 25 subjects did not. The seven patients with OHS all had sleep apnea. Of the 25 without OHS, 23 had sleep apnea. Subjects with OHS had significantly greater oxyhemoglobin desaturation during sleep than subjects without OHS, even when subjects with and without OHS were matched for sex and weight. These findings are consistent with the hypothesis that severe sleep apnea is a contributing cause of OHS.