We evaluated the benefits of O2 therapy and nocturnal nasal positive pressure ventilation (NPPV) with or without O2 in patients with severe chronic obstructive pulmonary disease (COPD). Twelve patients with severe COPD and nocturnal oxygen desaturation, who had not been receiving long-term O2 therapy and who could tolerate more than 2 wk of NPPV therapy, were enrolled in this study in a stable condition. Data on pulmonary function tests (PFTS), arterial blood gases (ABG), right and left ventricular ejection fractions (RVEF and LVEF) from nuclear medicine studies, and overnight sleep studies were collected at the beginning of the study and after each 2 wk of therapy with O2, NPPV, or NPPV with O2. Patients received O2 monotherapy or NPPV for sequential 2-wk periods in a randomized, cross-over design, followed by 2 wk of NPPV with O2. Hypoxic and hypercapnic ventilatory responses (HVR) in the study group, as measured by mouth occlusion pressure in the first 100 ms of inspiration against an occluded airway (P0.1), were compared with normal controls and repeated after 2 wk of therapy with NPPV with O2. The results revealed no significant changes in the percent of each sleep stage regardless of the treatment modality. However, sleep efficiency was poorer when NPPV was used than when it was not used. NPPV alone did not improve nocturnal oxygenation when compared with the baseline sleep study. Oxygen monotherapy was better than NPPV therapy for improving nocturnal oxygenation. NPPV plus O2 therapy showed no benefits over O2 monotherapy in either RVEF or LVEF, ABG, or HVR. In conclusion, for severe COPD patients, O2 therapy is more effective than NPPV for improving nocturnal oxygenation.