The low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions. This study tested the hypothesis that Tibetans resident at 4,200 m offset physiological hypoxia and achieve normal oxygen delivery by means of higher blood flow enabled by higher levels of bioactive forms of NO, the main endothelial factor regulating blood flow and vascular resistance. The natural experimental study design compared Tibetans at 4,200 m and U.S. residents at 206 m. Eighty-eight Tibetan and 50 U.S. resident volunteers (18 -56 years of age, healthy, nonsmoking, nonhypertensive, not pregnant, with normal pulmonary function) participated. Forearm blood flow, an indicator of systemic blood flow, was measured noninvasively by using plethysmography at rest, after breathing supplemental oxygen, and after exercise. The Tibetans had more than double the forearm blood flow of low-altitude residents, resulting in greater than sea level oxygen delivery to tissues. In comparison to sea level controls, Tibetans had >10-fold-higher circulating concentrations of bioactive NO products, including plasma and red blood cell nitrate and nitroso proteins and plasma nitrite, but lower concentrations of iron nitrosyl complexes (HbFe II NO) in red blood cells. This suggests that NO production is increased and that metabolic pathways controlling formation of NO products are regulated differently among Tibetans. These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia.circulation ͉ endothelium T he low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions (1-3). Hypothetically, the unavoidably low supply of oxygen in the air and the blood could be offset by increasing blood flow to improve oxygen delivery. Blood flow is determined by numbers, length, and diameter of blood vessels that in turn are largely determined directly or indirectly by levels of NO, a potent vasodilator synthesized in the endothelial cells lining the vessels (4-7). Tibetans have high levels of NO synthesis in the lungs (8), and pulmonary blood flow correlated with NO in a sample studied at 4,200 m (8, 9). This suggests the hypothesis that Tibetan highlanders offset hypoxia with higher systemic blood flow and higher levels of circulating, biologically active metabolites of NO. After synthesis by the endothelium, NO rapidly undergoes reaction in the blood to form products that have circulatory and metabolic effects, including nitrite, nitrate, nitrosothiol proteins (proteins containing NO-cysteine covalent bonds), and ␣-nitrosyl hemoglobin (HbFe II NO), in which NO occupies the heme binding site for o...