Objective: To determine the efficacy of acetazolamide in the treatment of patients with acute mountain sickness and the effect of the drug on pulmonary gas exchange in acute mountain sickness. Design: A randomized, double-blind, placebo-controlled trial. Setting: The Denali Medical Research Project high-altitude research station (4200 m) on Mt. McKinley, Alaska. Participants: Twelve climbers attempting an ascent of Mt. McKinley (summit, 6150 m) who presented to the medical research station with acute mountain sickness. Intervention: Climbers were randomly assigned to receive acetazolamide, 250 mg orally, or placebo at 0 (baseline) and 8 hours after inclusion in the study. Main Outcome Measures: An assessment of acute mountain sickness using a symptom score and pulmonary gas exchange measurements was done at baseline and at 24 hours. Main Results: After 24 hours, five of six climbers treated with acetazolamide were healthy, whereas all climbers who received placebo still had acute mountain sickness (P = 0.015). Arterial blood gas specimens were obtained from three of the six acetazolamide recipients and all of the placebo recipients. The alveolar to arterial oxygen pressure difference (PA(O2)-Pa(O2) difference) decreased slightly over 24 hours in the acetazolamide group (- 0.8 +/- 1.2 mm Hg) but increased in the placebo group (+ 3.3 +/- 2.3 mm Hg) (P = 0.024). Acetazolamide improved Pa(o2) over 24 hours (+ 2.9 +/- 0.8 mm Hg) when compared with placebo (- 1.3 +/- 2.8 mm Hg) (P = 0.045). Conclusion: In established cases of acute mountain sickness, treatment with acetazolamide relieves symptoms, improves arterial oxygenation, and prevents further impairment of pulmonary gas exchange.