High-intensity work might not be preserved in chronic obstructive pulmonary disease (COPD) during whole-body exercise due to ventilatory limitations that exceed metabolic limitations, resulting in reduced training adaptations. The purpose of the present study was to address the hyperoxic effect during training and testing in COPD patients with hypoxemia at peak exercise. Six COPD and eight coronary artery disease (CAD) patients completed 24 aerobic high-intensity interval training sessions, 4x4 min in hyperoxia at 85-95% of the peak heart rate and peak exercise tested in normoxia and hyperoxia pre- and post-training. VO2peak increased in the COPD group by 19% (13-31%) and in the CAD group by 15% (7-29%), [0.98(0.68-1.52)-1.17(0.89-1.78) and 2.11(1.57-2.64)-2.44(1.92-3.39) L/min], respectively. VO2peak was higher in hyperoxia at pre- and post-test (1.22(0.80-1.87) and 1.37(1.01-1.94) L/min) in the COPD group. Work economy improved by 10% in both groups. Quality of life improved in the COPD group in terms of physical and mental health status by 24% and 35%. Hyperoxic aerobic high-intensity interval training in COPD patients with hypoxemia at peak exercise increases VO2peak, peak workload, work economy and quality of life. Acute hyperoxia increases VO2peak, peak workload at pre- and post-test compared with normoxia in the COPD patients, indicating an oxygen supply limitation to VO2peak.