To determine whether the decreased hypoxic responses present in patients with hypoxemic chronic obstructive pulmonary disease (COPD) were reversible with correction of their hypoxemia, we measured ventilatory and P0.1 responses to CO2 and hypoxia in 30 such patients. These patients were then randomly allocated to either 24-h continuous oxygen or 12-h nocturnal oxygen therapy. Responses to CO2 and hypoxia were then remeasured in all patients after 6 months of oxygen therapy, and in 13 patients after 1 yr of oxygen therapy. The blunt hypoxic responses showed no increase after either regimen of oxygen therapy and were further reduced after 6 months of 12-h nocturnal oxygen. The decreased hypoxic response in patients with hypoxemic COPD appears nonreversible with the relief of the hypoxemia. Responses to CO2 were depressed after 6 months of 24-h oxygen therapy and associated with a significant increase in PaCO2. The change in PaCO2 after oxygen therapy was nonpredictable in terms of the initial responses to hypoxia or CO2. Minute ventilation (VE) and mean inspiratory flow during resting breathing at an arterial O2 saturation of 95% decreased after 6 months of 24-h oxygen therapy, indicating a reduction in central ventilatory drive.