The mechanisms responsible for the development of chronic hypercapnia in patients with obstructive sleep apnea (OSA) are not well defined. Therefore, we tested the hypothesis that diffuse airway obstruction may be involved by studying 50 patients with a well-documented OSA syndrome. Seven patients had daytime hypercapnia with a mean PaCO2 of 51 +/- 2 (SEM) mm Hg, compared to a PaCO2 of 35 +/- 1 in the other 43 patients. There were no differences between the 2 groups in the number or duration of nocturnal obstructive events. In contrast, the hypercapnic patients were significantly heavier than the normocapnic patients (body weight, 189 +/- 11 versus 148 +/- 6% of ideal; p less than 0.005) and had evidence of diffuse airway obstruction, as indicated by an increased residual volume and a reduction in all expiratory flow rates. When the hypercapnic patients were compared with a weight-matched group of 9 normocapnic patients (body weight, 196 +/- 8% of ideal), there were still no differences in nocturnal obstructive events, but the differences in tests of airway mechanics persisted. Multiple regression analysis of PaCO2 against several anthropometric, respiratory physiologic, and polysomnographic variables revealed that only 2 variables (expiratory reserve volume and FEV1/FVC), both of which are influenced by airway mechanics, were significantly correlated with PaCO2 (multiple r = 0.78; p = 0.0001). The findings suggest that OSA alone does not produce daytime hypercapnia even in obese patients, and that the presence of diffuse airway obstruction is an important predisposing factor to the development of chronic CO2 retention in such patients.