Background: Limited data are available comparing air travel with the hypoxia inhalation test (HIT) in passengers with COPD. The aim of this study was to assess the predictive capability of the HIT to in-flight hypoxemia in passengers with COPD. Methods: Thirteen passengers (seven female passengers) with COPD (mean [± SD], FEV1/FVC ratio, 44 ± 17%) volunteered for this study. Respiratory function tests were performed preflight. Pulse oximetry, cabin pressure, and dyspnea were recorded in flight. The HIT and a 6-min walk test were performed postflight. The in-flight oxygenation response was compared to the HIT results and respiratory function parameters. Results: All subjects flew without the use of oxygen, and no adverse events were recorded in-flight (mean cabin altitude, 2,165 m; altitude range, 1,892 to 2,365 m). Air travel caused significant desaturation (mean preflight oxygen saturation, 95 ± 1%; mean in-flight oxygen saturation, 86 ± 4%), which was worsened by activity (nadir pulse oximetric saturation [SpO 2], 78 ± 6%). The HIT caused mean desaturation that was comparable to that of air travel (84 ± 4%). The mean in-flight partial pressure of inspired oxygen (PIO2) was higher than the HIT PIO 2 (113 ± 3 mm Hg vs 107 ± 1 mm Hg, respectively; p < 0.001). The HIT SpO2 showed the strongest correlation with in-flight SpO2 (r = 0.84; p < 0.001). Conclusion: Significant in-flight desaturation can be expected in passengers with COPD. The HIT results compared favorably with the air travel data, with differences explainable by PIO 2 and physical activity. The HIT is the best widely available laboratory test to predict in-flight hypoxemia.