Hypoxia and hypercapnia have been shown to cause an increase in the concentration of vasopressin in plasma, but their effects on vasopressin in cerebrospinal fluid (CSF) are not known. In addition, the effect of metabolic acidosis on plasma and CSF vasopressin has not been reported. In this study, plasma and CSF vasopressin levels were measured in anesthetized dogs subjected to either hypoxia, hypercapnia, or metabolic acidosis. Rate and depth of respiration were closely regulated with the aid of muscle paralysis and mechanical ventilation. Vasopressin increased markedly in both plasma and CSF during severe hypoxia (10% O2) and during hypercapnia (10% CO2) but did not change during either mild (15% O2) or moderate (12.5% O2) hypoxia. Although mild hypoxia by itself did not affect either plasma or CSF vasopressin, it did potentiate the increase in plasma and CSF vasopressin that was induced by severe hypercapnia, thus suggesting that hypoxia and hypercapnia may exert synergistic effects on vasopressin secretion. Metabolic acidosis produced by slow intravenous infusion of 1 N hydrochloric acid decreased arterial pH to values comparable to those induced by hypercapnia and increased vasopressin in plasma; CSF vasopressin was unchanged. These results are consistent with the concept that the source of vasopressin secreted into plasma may be different from that secreted into CSF.