Rapid exposure of unacclimatized persons to high altitude causes the syndrome acute mountain sickness (AMS). Prophylactic treatment with frequent high doses of dexamethasone has been shown to prevent AMS. To determine whether lower, less frequent doses were effective in preventing AMS, 28 men between the ages of 18 and 32 were exposed to a stimulated altitude of 4,570 m for 45 h in a hypobaric chamber on two occasions while taking one of three doses of dexamethasone (4 mg, 1 mg, or .25 mg every 12 h) or a placebo in a double-blind, crossover design. The 4-mg dose of dexamethasone reduced the incidence of AMS symptoms compared with placebo and the other dose levels. Dexamethasone did not alter fluid balance or plasma volume changes, but treatment with 1 mg and 4 mg suppressed cortisol secretion. There was no evidence of adrenal cortical suppression after treatment with dexamethasone or placebo 48 h after discontinuing altitude exposure and drug treatment. The results indicate that 4 mg of dexamethasone twice daily is an effective prophylactic treatment for AMS, while lower doses are relatively ineffective.