The role of prostaglandins in the pathogenesis of acute mountain sickness and two hypoxia-induced vascular responses was evaluated using the cyclooxygenase inhibitor naproxen. Eleven men spent 24 hours at sea level, followed by 34 hours of decompression to 428 mm Hg while receiving naproxen (N), 250 mg twice daily or placebo (P) in a double-blind crossover trial. Serum naproxen levels measured by high pressure liquid chromatography were changed by hypoxia. The severity of acute mountain sickness (AMS) by the Environmental Symptom Questionnaire scores and observer assessment were unaffected by drug treatment. Retinal artery diameter measured from projected fundus photographs was increased after 27 hours at altitude (11.4 ± .5 mm) vs. sea level (9.4 ± .5 mm, p < 0.05) during both trials. Upright mean arterial pressure fell after 6 hours at altitude (79 ± 3 mm Hg during N and P vs. 92 ± 3 at sea level, p < 0.01). Minute ventilation, end expiratory alveolar PO2 and PCO2 did not differ between drug trials. This study suggests vasodilating prostaglandins do not have a major role in the genesis of AMS, hypoxia-induced retinal vasodilatation, or postural blood pressure responses in man.