BACKGROUND: Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. Cardiovascular adjustments to hypoxia are mediated, at least in part, by the sympathetic nervous system, and sympathetic activation promotes pulmonary vasoconstriction and alveolar fluid flooding in experimental animals. METHODS AND RESULTS: We measured sympathetic nerve activity (using intraneural microelectrodes) in 8 mountaineers susceptible to high-altitude pulmonary edema and 7 mountaineers resistant to this condition during short-term hypoxic breathing at low altitude and at rest at a high-altitude laboratory (4559 m). We also measured systolic pulmonary artery pressure to examine the relationship between sympathetic activation and pulmonary vasoconstriction. In subjects prone to pulmonary edema, short-term hypoxic breathing at low altitude evoked comparable hypoxemia but a 2- to 3-times-larger increase in the rate of the sympathetic nerve discharge than in subjects resistant to edema (P<0.001). At high altitude, in subjects prone to edema, the increase in the mean+/-SE sympathetic firing rate was >2 times larger than in those resistant to edema (36+/-7 versus 15+/-4 bursts per minute, P<0.001) and preceded the development of lung edema. We observed a direct relationship between sympathetic nerve activity and pulmonary artery pressure measured at low and high altitude in the 2 groups (r=0.83, P<0.0001). CONCLUSIONS: With the use of direct measurements of postganglionic sympathetic nerve discharge, these data provide the first evidence for an exaggerated sympathetic activation in subjects prone to high-altitude pulmonary edema both during short-term hypoxic breathing at low altitude and during actual high-altitude exposure. Sympathetic overactivation may contribute to high-altitude pulmonary edema.