Introduction: Altitude exposure will cause moderate to severe hypoxemia in patients with chronic obstructive pulmonary disease (COPD). Supplemental oxygen can be used to attenuate this hypoxemia; however, individual response is variable and difficult to predict. The aim of this study was to assess the efficacy of oxygen supplementation in patients with COPD at a barometric pressure similar to that of a commercial aircraft cabin. Methods: Following sea-level (40 m) arterial blood gases measurements, 18 patients with COPD were driven to altitude (2086 m), where blood gases were repeated at rest and while on 2 L·min-1 of supplementary oxygen (altitudeO2). Results: Ascent from sea level to altitude caused significant hypoxemia (75 ± 9 vs. 51 ± 6 mmHg), which was partially reversed by supplemental oxygen (64 ± 9 mmHg). Oxygen supplementation did not significantly alter PaCO2 levels (vs. altitude PaCO2). There was a significant relationship between the sea-level CaO 2 versus the altitudeO2 CaO2 (r = 0.89, P < 0.001). There was a significant relationship (r = 0.81, P < 0.001) between altitude-induced desaturation and resaturation with the administration of oxygen. There was a significant negative correlation (r = -0.74, P < 0.001) between baseline KCO and the improvement in CaO2 with the administration of oxygen. Conclusion: Low-flow supplemental oxygen during acute altitude exposure will partially reverse altitude-induced hypoxemia in patients with COPD. Patients with diffusion impairments are likely to experience the greatest altitude desaturation, but will gain the most benefit from supplemental oxygen. Supplemental oxygen, delivered at 2 L·min-1, should maintain clinically acceptable oxygenation during commercial air travel in patients with COPD.