Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T₂) 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). T₂ relaxation was estimated from a T₂ index of T₂-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.