Previous studies of brain glucose metabolism in people indigenous to high-altitude environments uncovered two response patterns: Quechuas native to the high Andes of South America sustained modest hypometabolism in most brain regions interrogated, whereas Sherpas, native to the Himalayas and considered by many biologists to be most effectively high-altitude adapted of all humans, showed brain metabolic patterns similar to lowlanders, with no acclimation effects noted. In the present study, the database was expanded to include hypoxia acclimation effects in lowlanders. Positron emission tomography (PET) and [¹⁸F]-2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMR_glc) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMR_glc were found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMR_glc. The observed short-term hypoxia acclimation responses in these lowlanders clearly differ from the long-term hypoxia adaptations found in brain metabolism of people indigenous to high-altitude environments.