Arterial desaturation in athletes during intense exercise has been reported by several authors, yet the etiology of this phenomenon remains obscure. Inadequate pulmonary ventilation, due to a blunted respiratory drive, has been implicated as a factor. To investigate the relationship between the ventilatory response to hypoxia, exercise ventilation, and arterial desaturation, 12 healthy male subjects [age, 23.8 +/- 3.6 yr; height, 181.6 +/- 5.6 cm; weight, 73.7 +/- 6.2 kg; and maximal O2 uptake (VO2max), 63.0 +/- 2.2 ml.kg-1 min-1] performed a 5-min treadmill test at 100% of VO2max, during which arterial blood samples and ventilatory data were collected every 15 s. Alveolar PO2 (PAO2) was determined using the ideal gas equation. On a separate occasion the ventilatory response to isocapnic hypoxia was measured. Arterial PO2 decreased by an average of 29 Torr during the test, associated with arterial desaturation [arterial O2 saturation (SaO2) 92.0%]. PAO2 was maintained; however, alveolar-arterial gas pressure difference increased progressively to greater than 40 Torr. Minimal hypocapnia was observed, despite marked metabolic acidosis. There was no significant correlation observed between hypoxic drives and ventilation-to-O2 uptake ratio or SaO2 (r = 0.1 and 0.06, respectively, P = NS). These data support the conclusions that hypoxic drives are not related to maximal exercise ventilation or to the development of arterial desaturation during maximal exercise.