Background: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established.Methods: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A•-], via electron paramagnetic resonance spectroscopy, and nitrite [NO2−], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n = 13, CMS+) and without CMS (n = 12, CMS−). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured flow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT).Results: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS− group (P andlt; .05), as indicated by elevated A•- (3,191 ± 457 arbitrary units [AU] vs 2,640 ± 445 AU) and lower NO2− (206 ± 55 nM vs 420 ± 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS+ group (A•-, 3,765 ± 429 AU; NO2−, 148 ± 50 nM) compared with both the CMS− group and lowlanders (P andlt; .05). This was associated with systemic vascular dysfunction as indicated by lower (P andlt; .05 vs CMS−) FMD (4.2% ± 0.7% vs 7.6% ± 1.7%) and increased AIx-75 (23% ± 8% vs 12% ± 7%) and carotid IMT (714 ± 127 μM vs 588 ± 94 μM).Conclusions: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.