Physiological adaptations to intermittent hypoxia (IH) conditioning are based on the cumulative effect of repeated IH exposures. The present study sought to test the hypothesis that acute IH exposures would promote arterial O2 delivery and regional tissue oxygenation. Changes in arterial O2 saturation (SaO2, oximeter), forearm muscle and cerebral tissue oxygenations (SmO2 and ScO2, near-infrared spectroscopy) were compared during five repeated hypoxia exposures (10±0.2% O2 for 5-min each) interposed with four-minute inhalation of room air in 11 healthy subjects (24±0.9 y). Baseline, prehypoxia partial pressure of end-tidal O2 (PETO 2, mass spectrometer) and SaO2 (107±2 mmHg and 97.3±0.3%) were decreased (P< 0.05) after the first bout as compared with those during normoxia prior to the second (94±2 mmHg and 96.2±0.4%) and the fifth (92±3 mmHg and 95.7±0.7%) episodes of IH exposures, whereas partial pressure of end-tidal CO2, tidal volume and breathing frequency were similar. Arterial O2 dissociation in terms of per unit decrease in PETO2 during hypoxia, i.e. the slope of SaO2/PETO2, was augmented (P = 0.0025) from 0.71±0.09%/mmHg during the first hypoxia bout to 1.39±0.15%/mmHg and 1.47±0.16%/mmHg during the second and the fifth bouts, respectively. Fractional muscle tissue O2 extraction rate (SmO2D, i.e. normalized difference between SaO2 and SmO2) progressively decreased (P< 0.01) during IH; however, fractional cerebral tissue O2 extraction rate (ScO2D, i.e. normalized difference between SaO2 and ScO2) did not decrease during hypoxia (P = 0.94). ScO2D during normoxia tended to increase (P = 0.089) following repeated IH exposures. We conclude that enhanced arterial O2 delivery with repeated IH exposures serves as a compensatory mechanism to potentiate O2 availability during hypoxia.