Aim: Evaluate the acute effects of non-invasive positive pressure ventilation (NiPPV) during high-intensity exercise on endothelial function in patients with coexisting chronic obstructive pulmonary disease (COPD) and heart failure (HF). Methods: This is a randomized, double blinded, sham-controlled study involving 14 COPD-HF patients, who underwent a lung function test and Doppler echocardiography. On two different days, patients performed incremental cardiopulmonary exercise testing (CPET) and two constant-work rate tests (80% of CPET peak) receiving Sham or NiPPV (bilevel mode - Astral 150) in a random order until the limit of tolerance (Tlim). Endothelial function was evaluated by flow mediated vasodilation (FMD) at three time points: 1) Baseline; 2) immediately post-exercise with NiPPV; and 3) immediately post-exercise with Sham. Results: Our patients had a mean age of 70 ± 7 years, FEV1 1.9 ± 0.7 L and LVEF 41 ± 9%. NIPPV resulted in an increased Tlim (NiPPV: 130 ± 29s vs Sham: 98 ± 29s p = 0.015) and SpO2 (NiPPV: 94.7 ± 3.5% vs Sham: 92.7 ± 5.2% p = 0.03). Also, NiPPV was able to produce a significant increase in FMD (%) (NiPPV: 9.2 ± 3.1 vs Sham: 3.6 ± 0.7, p < 0.05), FMD (mm) (NiPPV: 0.41 ± 0.18 vs Sham: 0.20 ± 0.11, p < 0.05), Blood flow velocity (NiPPV: 33 ± 18 vs Baseline: 20 ± 14, p < 0.05) and Shear Stress (SS) (NiPPV: 72 ± 38 vs Baseline: 43 ± 25, p < 0.05). We found correlation between Tlim vs. ΔSS (p = 0.03; r = 0.57). Univariate-regression analysis revealed that increased SS influenced 32% of Tlim during exercise with NiPPV. Conclusion: NiPPV applied during high-intensity exercise can acutely modulate endothelial function and improve exercise tolerance in COPD-HF patients. In addition, the increase of SS positively influences exercise tolerance.