Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial P_CO2 (P_aCO2), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in P_aCO2 or intravascular bicarbonate ([HCO₃^–]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO₂ reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in P_aCO2 (hypocapnia: –5, –10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO₃^–; 8.4%, 50 mEq 50 mL^–1) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO₃^–] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L^–1; P < 0.001). Absolute CBF was not different at each stage of CO₂ reactivity (P = 0.629) following NaHCO₃^–, irrespective of a higher pH (P < 0.001) at each matched stage of P_aCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg P_aCO2; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg P_aCO2; P = 0.151) reactivity to P_aCO2 were altered pre- to post-NaHCO₃^–. When indexed against arterial [H⁺], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO₃^–, respectively. These changes in reactivity to [H⁺] were, however, explained by alterations in buffering between P_aCO2 and arterial H⁺/pH consequent to NaHCO₃^–. Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min^–1, 7% ± 12%; P = 0.047) following NaHCO₃^– during isocapnic breathing providing support for a direct influence of HCO₃^– on cerebrovascular tone independent of P_aCO2. These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by P_aCO2 rather than arterial pH.