Ambulatory oxygen therapy (AOT) is commonly prescribed in Interstitial Lung Disease (ILD) patients, with the aim of reducing dyspnea and increasing exercise tolerance. Despite its frequent use and a reasonable physiological rationale, there is a lack of evidence supporting the effect of AOT on improving dyspnea during exercise. Moreover, dyspnea encompasses distinct sensory (intensity, quality) and affective (anxiety, fear) components with different underlying neurophysiological mechanisms. The aim of this study was to evaluate the effect of oxygen supplementation on exercise tolerance and dyspnea in ILD patients with exercise induced hypoxia (EIH). Forty-seven ILD patients performed a six minute walk test (6MWT) on room air (RA) and with oxygen supplementation (Ox). The 6MWT distance (6MWD) was significantly greater with oxygen supplementation (RA: 242±143 m vs Ox: 345±106 m p<0,01). With oxygen supplementation, the overall dyspnea and anxiety significantly decreased both at rest (1,1±1,4 Borg Unit (BU) vs 0,4±0,9BU , p.<0.01, and 1,1±1,6BU vs 0,5±1,3 BU, p.<0.05, respectively) and at the end of exercise (5,1±2,6 BU vs 3,7±2,5 BU, p.<0.001 and 3,4 ±2,9 vs 2,5 ±2,8, p.<0.01, respectively) despite a greater walked distance. In ILD patients with EIH, oxygen supplementation increases the exercise tolerance and reduces overall dyspnea perception and the anxiety component of breathlessness.