In patients with chronic obstructive pulmonary disease (COPD), one of the proposed mechanisms for improving exercise tolerance, when work of breathing is experimentally reduced, is redistribution of blood flow from the respiratory to locomotor muscles. Accordingly, we investigated whether exercise capacity is improved on the basis of blood flow redistribution during exercise while subjects are breathing heliox (designed to primarily reduce the mechanical work of breathing) and during exercise with oxygen supplementation (designed to primarily enhance systemic oxygen delivery but also to reduce mechanical work of breathing). Intercostal, abdominal, and vastus lateralis muscle perfusion were simultaneously measured in 10 patients with COPD (forced expiratory volume in 1 s: 46 ± 12% predicted) by nearinfrared spectroscopy using indocyanine green dye. Measurements were performed during constant-load exercise at 75% of peak capacity to exhaustion while subjects breathed room air and, then at the same workload, breathed either normoxic heliox (helium 79% and oxygen 21%) or 100% oxygen, the latter two in balanced order. Times to exhaustion while breathing heliox and oxygen did not differ (659 ± 42 s with heliox and 696 ± 48 s with 100% O2), but both exceeded that on room air (406 ± 36 s, P < 0.001). At exhaustion, intercostal and abdominal muscle blood flow during heliox (9.5 ± 0.6 and 8.0 ± 0.7 ml · min-1·100 g-1, respectively) was greater compared with room air (6.8 ± 0.5 and 6.0 ± 0.5 ml·min -1·100-g, respectively; P < 0.05), whereas neither intercostal nor abdominal muscle blood flow differed between oxygen and air breathing. Quadriceps muscle blood flow was also greater with heliox compared with room air (30.2 ± 4.1 vs. 25.4 ± 2.9 ml·min-1·100 g-1; P < 0.01) but did not differ between air and oxygen breathing. Although our findings confirm that reducing the burden on respiration by heliox or oxygen breathing prolongs time to exhaustion (at 75% of maximal capacity) in patients with COPD, they do not support the hypothesis that redistribution of blood flow from the respiratory to locomotor muscles is the explanation.