Background: Systemic hypoxia elicits various changes in human body, which leads to acclimatization of human to the condition. However, there is no evidence that systemic hypoxia without ischemic injury mobilizes endothelial progenitor cells (EPCs). In the present study, we investigated whether systemic hypoxia recruit EPCs into human peripheral blood. Methods and results: Twelve healthy volunteers who were undergoing an aircrew training course experienced hypobaric hypoxia in a hypobaric chamber under monitoring of electrocardiogram, blood pressure, oxygen saturation and mental status. They were exposed to hypoxia equal to the altitude of 4,600m (estimated PaO2: 45 mmHg, measured O2 saturation was 80짹4%) for 30 minutes. Blood samples were obtained before and 6 h after exposure. Levels of VEGF, IL-8, MCP-1, SDF-1, G-CSF and EPO were measured using ELISA. Circulating EPCs (AC133+ or CD34+/KDR+) in the peripheral blood were quantified using flow cytometry. We performed EPC culture in vitro and compared the size and number of the EPC colonies. We found that the levels of VEGF were significantly increased 6 h after hypoxia exposure (VEGF: 257.2짹43.5 to 360.9짹59.1 pg/mL, p=0.034). IL-8, however, was decreased (32.0짹8.0 to 21.9짹7.6, p=0.028) whereas the levels of MCP-1, SDF-1, G-CSF and EPO were not changed (p>0.05). The number of AC133+ or KDR+/CD34+ cells was increased 6h after hypoxia (AC133+ cells: 1740짹560 to 3160짹1280/mL, p=0.048; KDR+/CD34+ cells: 590짹400 to 870짹450/mL, p=0.016). In addition, the size and number of EPCs colonies were also increase after exposure to hypoxia (colony count: 10.7짹1.7/LPF at pre-exposure to 15.8짹1.8/LPF at 6 h, p=0.003). Conclusion: EPCs were acutely increased in the human peripheral blood after systemic hypoxia. The increase of EPCs may be a physiologic response to hypoxia which possibly contributes to hypoxia adaptation.