Objective The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). Methods Thirteen males age = (26 (sd 6)) years were exposed to normobaric hypoxia (12% O2) and normoxia (21% O2). After 2 and 10 hours, AMS symptoms were assessed alongside ventricular and venous vessel volumes, cerebral blood flow, regional brain volumes, and intracranial pressure, using high-resolution magnetic resonance imaging. Results In normoxia, neither lateral ventricular volume (R2 = 0.07, p = 0.40) nor predominance of unilateral transverse venous sinus drainage (R2 = 0.07, p = 0.45) was related to AMS symptoms. Furthermore, despite an increase in cerebral blood flow after 2 hours of hypoxia (hypoxia vs normoxia: Δ148ml/min−1, 95% confidence interval [CI] = 58 to 238), by 10 hours, when AMS symptoms had developed, cerebral blood flow was normal (Δ−51ml/min−1, 95% CI = −141 to 39). Conversely, at 10 hours brain volume was increased (Δ59ml, 95% CI = 8 to 110), predominantly due to an increase in gray matter volume (Δ73ml, 95% CI = 25 to 120). Therefore, cerebral spinal fluid volume was decreased (Δ−40ml, 95% CI = −67 to −14). The intracranial pressure response to hypoxia varied between individuals, and as hypothesized, the most AMS-symptomatic participants had the largest increases in intracranial pressure (AMS present, Δ7mmHg, 95% CI = −2.5 to 17.3; AMS not present, Δ−1mmHg, 95% CI = −3.3 to 0.5). Consequently, there was a significant relationship between the change in intracranial pressure and AMS symptom severity (R2 = 0.71, p = 0.002). Interpretation The data provide the strongest evidence to date to support the hypothesis that the “random” nature of AMS symptomology is explained by a variable intracranial pressure response to hypoxia. ANN NEUROL 2014