In order to investigate whether the changes in Pa_O2 reported during acid-base disturbances are due to modifications of ventilation/perfusion relationships or only to extrapulmonary factors, we studied the hemodynamics and blood gases of eight critically ill patients maintained in constant mechanical ventilation, before and after selective correction of metabolic alkalosis by infusion of 1 N hydrochloric acid (HCl). HCl infusion decreased arterial pH from 7.55 to 7.40 (p < 0.001) and increased Pa_O2 from 76 to 98 mm Hg (p < 0.05) at the end of the study. Cardiac output and oxygen consumption did not change. In patients with initial venous admixture (s/t) < 20% (n = 4), s/t did not change, and hemoglobin saturation decreased, whereas Pa_O2 increased from 87 to 96 mm Hg (p < 0.10), indicating a shift in the oxyhemoglobin dissociation curve caused by the Bohr effect. In patients with s/t > 20% (n = 4), s/t decreased from 27 to 22% (p < 0.05), hemoglobin saturation increased from 93 to 96% (p < 0.05), and Pa_O2 increased from 65 to 100 mm Hg (p < 0.05), which reflects an improvement in ventilation/perfusion relationships, probably because of enhanced hypoxic pulmonary vasoconstriction. These data indicate that metabolic alkalosis deteriorates pulmonary ventilation/perfusion relationships in patients with marked respiratory failure (s/t > 20%), and that reversing this effect with HCl infusion can improve Pa_O2 significantly.