This study aimed to evaluate the putative effects of hypobaria on ventilatory, cardiovascular, and muscle oxygenation during exercise in normoxia and hypoxia. Eighteen healthy air pilot trainees (26 ± 3 yr, 177 ± 10 cm, 70 ± 11 kg) performed a 6-min moderate-intensity cycling exercise (1 W/kg) in four randomized conditions, namely, normobaric normoxia (NN), hypobaric normoxia (HN), normobaric hypoxia (NH), and hypobaric hypoxia (HH) in a hypobaric chamber. Inspired oxygen pressure was matched between normoxic (NN vs. HN, 141.2 ± 0.8 vs. 141.5 ± 1.5 mmHg) and hypoxic (NH vs. HH, 75.7 ± 0.4 vs. 74.3 ± 1.0 mmHg) conditions. Gas exchanges, pulse oxygen saturation ([Formula: see text]), heart rate, middle cerebral artery blood flow velocity, cerebral and muscular oxygenation, and cerebral O ₂ delivery (cDO ₂ ) were recorded. [Formula: see text], brain, and muscle oxygenation were significantly lower and ventilation higher in HH than in NN and HN, and NH, during both rest and exercise (exercise [Formula: see text] 99.0 ± 1.5, 80.8 ± 4.2, 97.6 ± 1.9, and 69.2 ± 5.7% and ventilation 12.5 ± 2.3, 13.3 ± 3.1, 12.4 ± 2.6, and 14.6 ± 2.4 L/min in NN, NH, HN, and HH, respectively). cDO ₂ was decreased to the same extent in HH and NH compared with NN and HN (exercise 865.5 ± 147.6, 731.8 ± 152.2, 857.8 ± 157.8, and 755.8 ± 163.3 cm·mLO ₂ /s·dL _bl ). Specific effects of hypobaria in normoxia were lesser than in hypoxia since only blood O ₂ and CO ₂ partial pressures were lower in HN than NN. Respiratory and cardiovascular responses and brain/muscle oxygenation were more altered in HH than in NH, which confirms the additive effects of hypobaria on exercise in severe hypoxia. However, the effects of hypobaria are likely of negligible clinical relevance in normoxia.NEW & NOTEWORTHY A hypobaric normoxia (HN) condition was used to disentangle the effects of hypoxia and hypobaria. There was an additive effect of hypobaria and hypoxia. Cerebral and muscular tissue oxygenation were lower in hypobaric normoxia than in normobaric hypoxia during rest and exercise. The effects of hypobaria were negligible in normoxia.