In this study we have determined the effect of severe and moderate hypoxemia on plasma hypoxanthine and lactate values. Hypoxemia was induced in healthy humans in a low pressure chamber. The test subjects breathed atmospheric air at barometric pressures of 279 mm Hg and 385 mm Hg, representing a simulated altitude of about 7,620 and 5,334 m (25,000 and 17,500 ft), respectively. Exposure to 279 mm Hg represents a severe hypoxemia and all subjects exposed to this simulated altitude for 2 min showed symptoms related to hypoxia. After this exposure, plasma hypoxanthine increased by an average of 2.4 times compared to preexposure values. Exposure to 385 mm Hg represents a moderate hypoxemia and the persons tested at this simulated altitude for 45 min showed no or minor symptoms related to hypoxia and there was no change in plasma hypoxanthine values. In contrast to the unchanged plasma hypoxanthine values there was a 50% increase in plasma lactate values after 30 min exposure. We conclude that plasma hypoxanthine is a reliable marker for severe cellular hypoxia in humans and that enhanced plasma hypoxanthine levels are a rapid response to cellular hypoxia.