Acute mountain sickness (AMS) and high-altitude cerebral edema share common clinical characteristics suggesting cerebral swelling may be an important factor in the pathophysiology of AMS. Hypoxia and hypocapnia associated with high altitude are known to exert strong effects on the control of the cerebral circulation, yet how these effects interact during acute hypoxia, and whether AMS susceptible subjects may have a unique response, is still unclear. To test if self-identified AMS-susceptible individuals show altered brain swelling in response to acute hypoxia, we used quantitative arterial spin-labeling and volumetric MRI to measure cerebral blood flow (CBF) and cerebrospinal fluid (CSF) volume changes during 40-minutes of acute hypoxia. We estimated changes in cerebral blood volume (CBV) (from changes in CBF) and brain parenchyma swelling (from changes in CBV and CSF). Subjects with extensive high-altitude experience in two groups participated: self-identified AMS-susceptible (AMS-S, n=6) who invariably experienced AMS at altitude and self-identified AMS-resistant (AMS-R, n=6) who almost never experienced symptoms. During 40-minutes hypoxia, intracranial cerebrospinal fluid volume decreased significantly (-10.5 (SD 6.9) ml, P < 0.001). There were significant increases in cerebral blood volume (+2.3 (SD 2.5) ml, P < 0.005), and brain parenchyma volume (+8.2 (SD 6.4) ml, P < 0.001). However, there was no significant difference between self-identified AMS-susceptible and AMS-resistant groups for these acute-phase changes. In acute hypoxia, brain swelling occurs earlier than previously described, with significant shifts in intracranial cerebrospinal fluid occurring as early as 40-minutes after exposure. These acute-phase changes are present in all individuals irrespective of susceptibility to AMS.