Cardiovascular (CV) morbidity and mortality are increased in patients suffering from diseases associated with chronic hypoxemia. The contribution of hypoxemia per se has proven difficult to determine, because these patients often present several additional CV risk factors. Chronic mountain sickness (CMS) is characterized by chronic hypoxemia, affects subjects with a low CV risk profile and thereby provides a unique opportunity to study the independent effects of chronic hypoxemia on vascular function. We measured arterial oxygen saturation (SaO₂), flow-mediated dilation (FMD) of the brachial artery, carotid-femoral pulse wave velocity (PWV) and carotid intima-media thickness (IMT) in 23 CMS patients and 27 controls permanently living at 3600 m. The main new finding was that CMS patients (SaO₂ 83±3 vs. 90±3% in controls, P<0.0001) displayed marked systemic vascular dysfunction as evidenced by decreased FMD (4.6±1.2 vs. 7.6±1.9%, P<0.0001) and increased PWV (10.6±2.1 vs. 8.4±1.0 m/s, P<0.001) and IMT (690±120 vs. 570±110 μm, P=0.001). Oxygen administration almost completely restored FMD in CMS patients but had no effect in controls. These data demonstrate for the first time that chronic hypoxemia per se induces systemic vascular dysfunction in humans. We speculate that improving arterial oxygenation per se has favorable effects on CV morbidity and mortality in chronically hypoxemic patients.