Positive expiratory pressure (PEP) has been shown to limit hypoxia-induced reduction in arterial oxygen saturation, but its effectiveness on systemic and cerebral adaptations, depending on the type of hypoxic exposure [normobaric (NH) versus hypobaric (HH)], remains unknown. Thirteen healthy volunteers completed three randomized sessions consisting of 24-h exposure to either normobaric normoxia (NN), NH (inspiratory oxygen fraction, [Formula: see text] = 13.6%; barometric pressure, BP = 716 mmHg; inspired oxygen partial pressure, [Formula: see text] = 90.9 ± 1.0 mmHg), or HH (3,450 m, [Formula: see text] = 20.9%, BP = 482 mmHg, [Formula: see text] = 91.0 ± 0.6 mmHg). After the 6th and the 22nd hours, participants breathed quietly through a facemask with a 10-cmH 2 O PEP for 2 × 5 min interspaced with 5 min of free breathing. Arterial ([Formula: see text], pulse oximetry), quadriceps, and cerebral (near-infrared spectroscopy) oxygenation, middle cerebral artery blood velocity (MCAv; transcranial Doppler), ventilation, and cardiovascular responses were recorded continuously. [Formula: see text]without PEP was significantly lower in HH (87 ± 4% on average for both time points, P < 0.001) compared with NH (91 ± 3%) and NN (97 ± 1%). PEP breathing did not change [Formula: see text] in NN but increased it similarly in NH and HH (+4.3 ± 2.5 and +4.7 ± 4.1% after 6h; +3.5 ± 2.2 and +4.1 ± 2.9% after 22h, both P < 0.001). Although MCAv was reduced by PEP (in all sessions and at all time points, −6.0 ± 4.2 cm/s on average, P < 0.001), the cerebral oxygenation was significantly improved ( P < 0.05) with PEP in both NH and HH, with no difference between conditions. These data indicate that PEP could be an attractive nonpharmacological means to improve arterial and cerebral oxygenation under both normobaric and hypobaric mild hypoxic conditions in healthy participants.