Background and Aims: Patients with chronic mountain sickness (CMS) are predisposed to premature cardiovascular disease and severe arterial hypoxaemia though the underlying mechanisms remain unclear (Penaloza and Arias-Stella, 2007). The present study examined if [1] CMS is characterised by exaggerated oxidative-nitrosative stress as indicated by an increased systemic accumulation of free radicals and corresponding reduction in nitric oxide (NO) bioavailability and [2] whether this was related to impaired vascular structure and function. Methods: Thirteen male patients with primary CMS (CMS+) and 13 healthy age-matched native highlanders (CMS-) were examined at 3,600 m (La Paz, Bolivia). To place the magnitude of the oxidative-nitrosative stress response in highlanders into clearer perspective, we also examined 12 age and activity-matched healthy male lowlanders at sea-level and during acute exposure to simulated high-altitude. A resting venous sample was obtained from a cephalic vein following a 12 h overnight fast. Oxidative-nitrosative stress was assessed using the combined application of electron paramagnetic resonance spectroscopy (ascorbate radical as a marker of global flux and spin-trapped lipid radicals as a determinant of lipid peroxidation) and (modified tri-iodide) ozone-based chemiluminescence (NO metabolites) as previously described (Bailey et al., 2011). Since oxidative stress has been shown to induce vascular dysfunction (Bailey et al., 2009), we also assessed flow-mediated dilatation (FMD), arterial stiffness (AIx-75) and carotid intima-media thickness (IMT). Results: Oxidative-nitrosative stress was moderately elevated (↑ascorbate radicals, ↑lipid radicals and ↓nitrite, ↓NO) in CMS- (P < 0.05 vs. normoxic lowlanders) and comparable to that observed during acute hypoxic exposure in healthy lowlanders in whom vascular dysfunction is typically observed. Despite this, vascular function remained preserved. In contrast, oxidative-nitrosative stress was markedly exaggerated in CMS+ (P < 0.05 vs. CMS- and lowlanders) and was associated (r = 0.48 to -0.63, P < 0.05) with systemic vascular dysfunction as indicated by a lower FMD and increased AIx-75 and carotid IMT (P < 0.05 vs. CMS-). Conclusions: These findings suggest that a moderate sustained increase in oxidative-nitrosative stress likely represents a physiological adaptive response to chronic hypoxia. However, when excessive, as in chronically hypoxaemic highlanders with CMS, it may prove maladaptive given its association with vascular dysfunction. Clinical Trials Gov Registration # NCT01182792