Hypoxia plays a key role in the pathogenesis of acute mountain sickness (AMS), but individual susceptibility is variable and cerebral symptoms do not always correlate with PaO₂ measurements. Cerebral hypoxia may be more relevant than PaO₂. We studied trends in cerebral regional oxygen saturation by the technique of near-infrared spectroscopy in 20 subjects ascending rapidly to 4680 m. Subjects were enrolled in a placebo-controlled, double-blind trial of medroxyprogesterone for the prevention of AMS. The fall in cerebral oxygen saturation was less than in the periphery. At 4680 m, cerebral oxygenation correlated with peripheral saturation but not with PaCO₂ or with cerebral symptoms scores. At 4680 m, subjects on medroxyprogesterone had higher cerebral and peripheral saturation compared with those on a placebo. We conclude that cerebral oxygenation monitored with the Critikon 2020 system provided important information on the complex relationship of hypoxia to AMS and that other factors, such as changes in blood flow or capillary permeability, may be equally important.