An altered acid-base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO 2 sensitivity at high altitude. Likewise, if [H + ] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO 2 (termed cerebrovascular CO 2 reactivity). However, the effect altered acid-base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO 2 remains unclear. We measured ventilation (V E ), middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, restingV E , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O 2 and CO 2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO 2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg −1 ; P < 0.01) andV E CO 2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min −1 mmHg −1 ; P < 0.01). Likewise, the hypocapnic MCAv CO 2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg −1 ; P < 0.01). The hypercapnic MCAv CO 2 reactivity correlated with resting pH at high altitude (R 2 = 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R 2 = 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO 2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO 2 reactivity and central chemoreflex may be partly attributed to an acid-base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid-base balance in the regulation in CBF and ventilatory control. Abbreviations CBF, cerebral blood flow; CVCi, cerebrovascular conductance index; MCAv, middle cerebral artery velocity; MAP, mean arterial blood pressure; SBE, standard basic excess;V E , ventilation.