Rationale. Chronic obstructive pulmonary disease (COPD) and heart failure (HF) coexist in approximately one third of patients presenting with one of these conditions. From a clinical standpoint, impaired tissue oxygen (O2) delivery stands as a common pathological mechanism of these cardiorespiratory diseases. Recent evidence suggest that muscle and cerebral blood flow and oxygenation are further impaired during exercise in patients with COPD-HF overlap compared to isolated diseases. However, it remains unknown whether impaired O2 delivery is associated with exaggerated manifestations of peripheral and central fatigue in COPD-HF overlap. In addition, improving cardiopulmonary interactions through non invasive positive pressure ventilation or through the addition of a hyperoxic gas mixture during exercise have been associated with enhanced cerebral and muscle O2 delivery and oxygenation in patients with COPD or HF. It is, therefore, conceivable that improved O2 delivery to these structures have beneficial influence on exercise capacity in patients with COPD-HF overlap due to less peripheral and central fatigue. Aims. To investigate the influence of impaired O2 delivery during exercise, and its alleviation with different interventions (non invasive positive pressure ventilation or hyperoxia), on neuromuscular fatigue in patients with COPD-HF.