Background: We sought to assess whether noninvasive ventilation (NIV) as an adjunct with high-intensity exercise (HIEx) is more effective than exercise alone or exercise + sham on respiratory and peripheral oxygenation and vascular function in subjects with coexisting COPD and heart failure (HF). Methods: On separate days, subjects performed incremental cardiopulmonary exercise testing and 3 constant load tests: HIEx, HIEx+NIV, and HIEx+sham (bi-level mode, Astral 150). Subjects were randomized with a 1:1 block allocation for the HIEx+NIV group and HIEx+sham group until the limit of tolerance (Tlim). Peripheral and respiratory oxygenation were assessed by oxyhemoglobin (O2Hb) and deoxyhemoglobin (Hb) using near-infrared spectroscopy in the respiratory and peripheral musculature. Vascular function was assessed by endothelial function using the flow-mediated vasodilation (FMD) method. Results: There was a significant increase in FMD (mm), FMD (%), and shear stress in the HIEx+NIV group when compared to HIEx or HIEx+sham (P textless .05). Less extraction of O2 (Hb) in the peripheral and respiratory muscles was observed in the HIEx+NIV group (P textless .05). We also found correlations between peripheral muscle oxygenation (O2Hb) at the moment 80% of Tlim (r = 0.71, P = .009) and peak of Tlim (100%) (r = 0.76, P = .004) with absolute FMD (mm) immediately after HIEx+NIV. Conclusions: NIV as an adjunct to HIEx can acutely unload the respiratory musculature with better redistribution of available blood flow and beneficially modulate endothelial function. These results may influence the approach to cardiopulmonary rehabilitation in patients with coexisting COPD-HF.