Seventeen fit women ran to exhaustion (14 +/- 4 min) at a constant speed and grade, reaching 95 +/- 3% of maximal O(2) consumption. Pre- and postexercise lung function, including airway resistance [total respiratory resistance (Rrs)] across a range of oscillation frequencies, was measured, and, on a separate day, airway reactivity was assessed via methacholine challenge. Arterial O(2) saturation decreased from 97.6 +/- 0.5% at rest to 95.1 +/- 1.9% at 1 min and to 92.5 +/- 2.6% at exhaustion. Alveolar-arterial O(2) difference (A-aDO(2)) widened to 27 +/- 7 Torr after 1 min and was maintained at this level until exhaustion. Arterial PO(2) (Pa(O(2))) fell to 80 +/- 8 Torr at 1 min and then increased to 86 +/- 9 Torr at exhaustion. This increase in Pa(O(2)) over the exercise duration occurred due to a hyperventilation-induced increase in alveolar PO(2) in the presence of a constant A-aDO(2). Arterial O(2) saturation fell with time because of increasing temperature (+2.6 +/- 0.5 degrees C) and progressive metabolic acidosis (arterial pH: 7.39 +/- 0.04 at 1 min to 7.26 +/- 0.07 at exhaustion). Plasma histamine increased throughout exercise but was inversely correlated with the fall in Pa(O(2)) at end exercise. Neither pre- nor postexercise Rrs, frequency dependence of Rrs, nor diffusing capacity for CO correlated with the exercise A-aDO(2) or Pa(O(2)). Although several subjects had a positive or borderline hyperresponsiveness to methacholine, this reactivity did not correlate with exercise-induced changes in Rrs or exercise-induced arterial hypoxemia. In conclusion, regardless of the degree of exercise-induced arterial hypoxemia at the onset of high-intensity exercise, prolonging exercise to exhaustion had no further deleterious effects on A-aDO(2), and the degree of gas exchange impairment was not related to individual differences in small or large airway function or reactivity.