Purpose: Endothelial function and carotid intima-media thickness (IMT), are established markers of vascular aging. Aim of the study was to investigate the presence of early markers of atherosclerosis in rural Sherpa population of Kumbu Valley (Nepal), in comparison with lowlanders Caucasian subjects. Methods: 99 Sherpa subjects, living at 2500-3800 m s.l. (34±12 years, BMI 24±3 kg/mq, mean BP 88±9 mmHg), free of cardiovascular disease and risk factors, were recruited, and compared to 60 Caucasian sea-level healthy volunteers (36±12 years, BMI 23±2 kg/mq, mean BP 86±8 mmHg). Endothelial function in the brachial artery (flow-mediated dilation, FMD, and response to glyceryl trinitrate, GTN), and carotid IMT were measured by automated edge-detection system. Left and right ventricular (LV and RV) systolic and diastolic function and pulmonary systolic pressure (PASP), and pulmonary vascular resistance (PVR) were evaluated by echocardiogram. In 11 subjects with reduced FMD, the protocol was repeated, after 100% O 2 administration for 1 hour, titrated to maintain O 2 saturation around 100%. Results: High-altitude group presented higher heart rate and lower pulse pressure than sea-level group. FMD was also reduced (5.2±3.1 vs 6.8±3.0%, p=0.01), despite similar brachial artery diameter (3.7±0.6 vs 3.6±0.7 mm, p=0.64), and response to GTN (8.3±3.1 vs 7.6±2.2%, p=0.13). Conversely, IMT was lower in high altitude group than in the sea-level group (0.51 vs 0.61 mm, p<0.001). Sherpa people showed normal LV and RV systolic and diastolic function, PASP(28±6 mmHg) and PVR (0.16±0.4). In the overall population FMD (5.2±3.1%) was not correlated to O 2 saturation (r=-0.03, p=0.74) and was similar in people with O 2 saturation >90% and in those <90% (5.3 vs 5.0%, p=0.74). In the subgroup receiving O 2 administration, FMD (from 3.1±2.5 to 3.8±2.6, p=0.46), response to GTN (from 8.9±2.7 to 8.7±1.9%), and echocardiographic parameters remained unchanged. Conclusions: Endothelial function is reduced in healthy Sherpa high-altitude dwellers, in the presence of normal RV and LV function and pulmonary pressures, independently of cardiovascular risk factors and hypoxia. This finding is accompanied with a lower IMT and might represent a physiological adaptation to high altitude.