Although hyperventilation is a well-known compensatory mechanism in metabolic acidosis, compensatory hypoventilation has been inconsistent and controversial in metabolic alkalosis. Six healthy subjects were studied under baseline conditions and during steady-state metabolic acidosis (seven episodes) and alkalosis (14 episodes). Minute ventilation (VE) fell in metabolic alkalosis and rose in metabolic acidosis. These changes in ventilation were entirely due to reduction and elevation of tidal volume (VT) respectively, while respiratory frequency (f) remained unchanged. Alveolar ventilation fell during metabolic alkalosis and resulted in elevation of arterial PCO2 in all subjects. The ventilatory response to arterial PCO2 in all subjects. The ventilatory response to CO2 breathing was also diminished. There was a linear relationship between PaCO2 and plasma [HCO-3] in metabolic acidosis and alkalosis which was defined as PaCO2 (mm Hg = 0.7 [HCO-a] + 20 (+/- SEM), r = 0.95. Although arterial PO2 and plasma [K+] fell during metabolic alkalosis, minute ventilation did not change upon breathing oxygen and there was no correlation between changes in plasma [K+] and plasma H+ regulation.