The presence of pulmonary, cerebral, and/or peripheral edema in acute mountain sickness (AMS) implies a derangement in the body’s handling of water. Previously, we demonstrated water retention and increased symptoms of AMS when hypocapnia was prevented in subjects exposed to simulated high altitude. This led us to the hypothesis that upon ascent to high altitude, those persons who fail to increase their ventilation adequately and hence do not become hypocapnic will retain water reflected as weight gain and will develop AMS. To test this hypothesis, we studied in Kathmandu, Nepal (1,377 m) 42 healthy western tourists; all were restudied in Pheriche (4,243 m) within 6 days of exposure to high altitude. Symptoms of AMS were highly correlated (p < 0.001) with weight change, suggesting that persons becoming symptomatic retained fluid. On going from low to high altitude, those persons who lost weight and remained well increased their resting ventilation, whereas those who gained weight did not (p = 0.03). This relative hypoventilation in the latter group was confirmed by higher values of Pco2 (heated hand vein blood) and lower values of arterial saturation (ear oximeter) at Pheriche. Vital capacity measured in Kathmandu was correlated with arterial saturation at Pheriche (p = 0.02); persons with low vital capacity were more hypoxemic with more symptoms of AMS. We conclude that relative hypoventilation and weight gain appear early in the development of AMS suggesting links between altitude hypoxia, hyperventilation, hypocapnia, and the body’s handling of wa