Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T(2)) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T(2) relaxation was estimated from a T(2) index of T(2)-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T(2,index) decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T(2,index) initially increased after 2 days, but decreased after 7 days. T(2,index) changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude.