When excessive, the increase in pulmonary artery systolic pressure (PASP) at high-altitude (HA) can lead to high-altitude pulmonary oedema (HAPE) with potentially fatal consequences. However, to what extent the pulmonary circulation contributes to the intravascular accumulation of free radicals and subsequent implications for pulmonary hypertension and susceptibility to altitude illness remains to be examined. Therefore, the current study examined if the increase in PASP at HA would be associated with a net trans-pulmonary output of free radicals and corresponding loss of nitric oxide (NO). Twenty six mountaineers provided central venous and radial arterial samples at low-altitude (LA) and within 20h following active ascent to the Capanna Regina Margherita located at 4559m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing and exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and high-sensitivity ELISA were employed for plasma detection of the ascorbate free radical (A●-), NO and 3-nitrotyrosine (3-NT) respectively. Ascent to HA increased PASP from 23 ± 4 to 38 ± 10mmHg (P < 0.05) which was more pronounced in subjects diagnosed with (severe) AMS (n = 11) and HAPE (n = 3) compared to subjects who remained free of illness (n = 8). HA increased the arterio-central venous concentration difference resulting in a net trans-pulmonary output or gain of A●- [HA: +715 ± 852 vs. LA: +137 ± 398 arbitrary units√Gauss/min, P < 0.05] and net uptake or loss of (total) NO (HA: -684 ± 661 vs. LA: +621 ± 778 nmol/min, P < 0.05). Exchange was more pronounced in AMS and HAPE (P < 0.05 vs. Healthy) and correlated against the rise in PASP (r = 0.69, P < 0.05) and arterial 3-NT (r = 0.46, P < 0.05). In conclusion, these findings are the first to suggest that a free radical-mediated reduction in pulmonary NO bioavailability (oxidative-nitrosative stress) may prove the unifying mechanism underlying HA-induced pulmonary hypertension and susceptibility to (AMS and) HAPE. These findings have broader implications for other human pulmonary diseases characterised by arterial hypoxaemia notably COPD.