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Changes in cerebral perfusion and CO2 cerebrovascular reactivity during and immediately after a sojourn at high altitude remain unclear but may be critical for acclimatization. The aim of the present study was to assess the effects of 6 days at 4350 m on cerebral perfusion and cerebrovascular reactivity (CVR) to CO2 by arterial spin labeling (ASL) magnetic resonance imaging at sea level and to compare it with transcranial Doppler (TCD) results at altitude. Eleven healthy male subjects, non-acclimatized to altitude, stayed for 6 days at 4350 m (Observatoire Vallot, massif du Mont-Blanc). Prior to the stay and within 6 h after returning to sea level, subjects were investigated using pseudo-continuous ASL at 3 T during a block-design inhalation paradigm to measure basal cerebral blood flow (CBF) and CO2 CVR. End-tidal CO2 (PetCO2), respiratory rate, heart rate and oxygen saturation were recorded during the exam. Subjects were also examined using TCD prior to and on day 5 of the stay at altitude to measure blood velocity in the middle cerebral artery (MCAv) and CO2 CVR. CO2 CVR was expressed as percent change in ASL CBF or TCD MCAv per mm Hg change in PetCO2. PetCO2 was significantly decreased during and after altitude. Significant increases in TCD MCAv compared to before altitude measurements were observed on day 5 at altitude (+ 20.5 A- 15.5%). Interestingly, ASL CBF remained increased in the MCA and anterior vascular territories (+ 22.0 A- 24.1% and 20.5 A- 20.3%, respectively) after altitude under normoxic conditions. TCD CVR tended to decrease on day 5 at 4350 m (a 12.3 A- 54.5% in the MCA) while the ASL CVR was significantly decreased after altitude (a 29.5 A- 19.8% in the MCA). No correlation was observed between cerebral hemodynamic changes and symptoms of acute mountain sickness at high altitude. In conclusion, prolonged exposure to high altitude significantly increases blood flow during the altitude stay and within 6 h after returning to sea level. Decreased CO2 CVR after prolonged altitude exposure was also observed using ASL. Changes in cerebral hemodynamics with altitude exposure probably involve other mechanisms than the vasodilatory effect of hypoxia only, since it persists under normoxia several hours following the descent.