Up to half of those who ascend rapidly to altitudes of over 3,000 m may experience symptoms of acute mountain sickness (AMS) and of these some 95% may suffer from high altitude headache. We report the first controlled trial specifically to assess an oral drug therapy for this common symptom. Subjects were 21 members of mountaineering expeditions to similar altitudes in the Bolivian Andes and the Himalayas in Nepal. The study was of a randomized, placebo-controlled, double-blind, within-patient crossover design. Ibuprofen was significantly superior to placebo both in reducing headache severity and in speed of relief (a mean difference of 94 min in time to no/minimal headache). Only 14% of subjects who initially took ibuprofen felt the need for further medication compared to 83% of those who took placebo first (p = 0.02). Of the 11 subjects completing both phases of the crossover, 8 (73%) favored ibuprofen while the remainder had no preference (p = 0.004). No attributable adverse effects occurred. The results suggest that ibuprofen is a safe and effective treatment for high altitude headache.