A healthy 36-year-old untrained (maximal oxygen consumption (V(O2max)): 39 mL/kg/min) woman completed multiple graded exercise tests on a treadmill. Temperature-corrected arterial blood samples were obtained in addition to esophageal pressure. Significant hypoxemia (-13 mm Hg arterial oxygen tension decrease) and arterial oxyhemoglobin desaturation (-6% decrease) was observed relative to rest and occurred during submaximal exercise and worsened at maximal intensities. Expiratory flow limitation (28-40% intersection of tidal volume) was present at near-maximal intensities. Relieving mechanical ventilatory constraints with a helium inspirate (79% He:21% O(2)) partially reversed the hypoxemia. Conversely, increasing chemical ventilatory stimuli, with hypercapnia (3.5% CO(2)), failed to increase ventilation. Maintaining oxyhemoglobin saturation, via a mildly hyperoxic (26% O(2)) inspirate, increased exercise duration (+45 s) and V(O2max) (+5 mL/kg/min). We attribute the hypoxemia to an excessive A-a(O2) resulting from ventilation-perfusion mismatch and secondarily to mechanical ventilatory constraints. We conclude that a healthy untrained woman can develop EIAH and this remains stable over a period of 6 months.