<b><i>Background:</i></b> Effects of hypobaric hypoxia at altitude on exercise performance of lowlanders with chronic obstructive pulmonary disease (COPD) have not been studied in detail. <b><i>Objectives:</i></b> To quantify changes in exercise performance and associated physiologic responses in lowlanders with COPD travelling to moderate altitude. <b><i>Methods:</i></b> A total of 31 COPD patients with a median age (quartiles) of 66 years (59; 69) and FEV₁ of 56% predicted (49; 69) living below 800 m performed a constant-load bicycle exercise to exhaustion at 60% of the maximal work rate at 490 m (Zurich) and at an identical work rate at 2,590 m (Davos) in randomized order. Pulmonary gas exchange, pulse oximetry (SpO₂), cerebral tissue oxygenation (CTO; near-infrared spectroscopy), and middle cerebral artery peak blood flow velocity (MCAv) by Doppler ultrasound during 30 s at end exercise were compared between altitudes. <b><i>Results:</i></b> With ascent from 490 to 2,590 m, the median endurance time (quartiles) was reduced from 500 s (256; 795) to 205 s (139; 297) by a median (95% CI) of 303 s (150–420) (<i>p</i> &#x3c; 0.001). End exercise SpO₂ decreased from 92% (89; 94) to 81% (77; 84) and CTO from 62% (56; 66) to 55% (50; 60); end exercise minute ventilation increased from 40.6 L/min (35.5; 47.8) to 47.2 L/min (39.6; 58.7) (<i>p</i> &#x3c; 0.05; all comparisons 2,590 vs. 490 m). MCAv increased similarly from rest to end exercise at 490 m (+25% [17; 36]) and at 2,590 m (+21% [14; 30]). However, the ratio of MCAv increase to SpO₂ drop during exercise decreased from +6%/% (3; 12) at 490 m to +3%/% (2; 5) at 2,590 m (<i>p</i> &#x3c; 0.05). <b><i>Conclusions:</i></b> In lowlanders with COPD travelling to 2,590 m, exercise endurance is reduced by more than half compared to 490 m in association with reductions in systemic and cerebral oxygen availability.