The physiological relevance of slow-wave vasomotion is still unclear, even though it has been hypothesized that it could be a compensatory mechanism for enhancing tissue oxygenation in conditions of reduced oxygen supply. The aim of our study was to explore the effects of hypoxia and ischemia on slow-wave vasomotion in microcirculation. Peripheral oxygen saturation and forearm microcirculation flow (laser-Doppler flowmetry) were recorded at baseline and during postocclusive reactive hyperemia in the Himalaya region from 8 European lowlanders (6 men; aged 29-39 yr) at 1,350, 3,400, and 5,050 m and from 10 Nepalese male highlanders (aged 21-39 yr) at 3,400 and 5,050 m of altitude. The same measurements were also performed at sea level in 16 healthy volunteers (aged 23-61 yr) during a short-term exposure to normobaric hypoxia. In lowlanders, exposure to progressively higher altitude under baseline flow conditions progressively increased 0.06-0.15 Hz vasomotion amplitude [power spectral density % was expressed as geometric means (geometric standard deviation) = 14.0 (3.6) at 1,350 m; 87.0(2.3) at 3,400 m and 249.8 (3.6) at 5,050 m; P = 0.006 and P < 0.001 vs. 1,350 m, respectively]. In highlanders, low frequency vasomotion amplitude was similarly enhanced at different altitudes [power spectral density % = 183.4 (4.1) at 3,400 m vs. 236.0 (3.0) at 5,050 m; P = 0.139]. In both groups at altitude, it was further increased after ischemic stimulus ( P < 0.001). At baseline, acute short lasting normobaric hypoxia did not induce low frequency vasomotion, which was conversely induced by ischemia, even under normal oxygenation and barometric pressure. This study offers the demonstration of a significant increase in slow-wave vasomotion under prolonged hypobaric-hypoxia exposure at high altitude, with a further enhancement after ischemia induction. NEW & NOTEWORTHY This study offers the demonstration in humans of the occurrence of enhanced slow-wave vasomotion in microcirculation induced by exposure to hypobaric hypoxia, ischemia, and their combination. This phenomenon, where vasomotion can be hypothesized to behave as a "peripheral heart," may represent a compensating adaptive change aimed at improving peripheral flow and tissue oxygenation in conditions of reduced oxygen supply, such as altitude-induced hypobaric hypoxia and postocclusion ischemia.