The possibility of persistent cerebral impairment due to exposure to extreme altitude and resulting hypoxic conditions is of great concern to both high altitude mountaineers and researchers. The aim of the present study was to investigate the effect of prolonged exposure to hypoxia on cerebral glucose metabolism, which probably precedes structural and functional impairment. Positron emission tomography (PET) employing [18F]-2-deoxy-2-fluoro-D-glucose (FDG) was performed, and the normobaric hypoxic ventilatory response (HVR) was assessed in 11 mountaineers before (pre) and after (post) climbing Mount Shisha Pangma (8048 m). During the climb, acute mountain sickness (AMS) symptoms were recorded and heart rate and oxygen saturation (SaO2) were measured daily. Neuropsychological evaluations were conducted at different heights. The difference FDGpost- FDGpre was analyzed voxel by voxel using statistical parametric mapping (SPM) and volumes of interest (VOI). SPM revealed two areas of increased cerebral FDG uptake after the expedition, one localized in the left cerebellum (+9.4%) and one in the white matter lateral of the left thalamus (+8.3%). The VOI analysis revealed increased postexpeditional metabolism in an area of the right cerebellum (+11%) and of the thalamus bilaterally (+3.7% on the left, +4.6% on the right). FDG-PET alterations did not correlate with changes in SaO2, HVR, or AMS scores. All neuropsychological test results during the climb were unremarkable. We conclude that a prolonged stay at an extreme altitude leads to regional specific changes in the cerebral glucose metabolism without any signs of neuropsychological impairment during the climb.