Acute mountain sickness (AMS) is a common condition occurring within hours of rapid exposure to high altitude. Despite its frequent occurrence, the pathophysiological mechanisms that underlie the condition remain poorly understood. We investigated the role of cerebral oxygen metabolism (CMRO2) in AMS. The purpose of this study was to test 1) if CMRO2 changes in response to hypoxia, and 2) if there is a difference in how individuals adapt to oxygen metabolic changes that may determine who develops AMS and who does not. Twenty-six normal human subjects were recruited into two groups based on Lake Louise AMS score (LLS): those with no AMS (LLS ≤ 2), and those with unambiguous AMS (LLS ≥ 5). [Subjects with intermediate scores (LLS 3–4) were not included.] CMRO2 was calculated from cerebral blood flow and arterial-venous difference in O2 content. Cerebral blood flow was measured using arterial spin labeling MRI; venous O2 saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Arterial O2 saturation was measured via pulse oximeter. Measurements were made during normoxia and after 2-day high-altitude exposure at 3,800 m. In all subjects, CMRO2 increased with sustained high-altitude hypoxia [1.54 (0.37) to 1.82 (0.49) μmol·g−1·min−1, n = 26, P = 0.045]. There was no significant difference in CMRO2 between AMS and no-AMS groups. End-tidal Pco2 was significantly reduced during hypoxia. Low arterial Pco2 is known to increase neural excitability, and we hypothesize that the low arterial Pco2 resulting from ventilatory acclimatization causes the observed increase in CMRO2.