Electrolyte composition of the cerebral spinal fluid (CSF) is important in central respiratory drive. The relationship between [Cl-] and [HCO3-] is of particular interest in maintenance of electrolyte balance. Therefore, the effect of furosemide, an inhibitor of sodium-coupled chloride transport, on CSF electrolyte homeostasis was studied under conditions of normocapnia and hypercapnia in anesthetized dogs. The drug was given intravenously (IV) or in the lateral cerebral ventricles (CV). With normocapnia, there was no change in CSF or arterial PCO2, pH, [K+], [Cl-], or [HCO3-], while CSF [NA+] decreased 1.7 mM in dogs receiving IV furosemide. With 5% CO2 breathing and IV furosemide, CSF PCO2, pH, [K+], [Cl-], and [HCO3-] changed as has been reported for 5% CO2 breathing alone. 5% CO2 and CV furosemide, however, led to a greater reduction in CSF [Cl-] and no change in CSF [HCO3-]. Thus CV furosemide alters the CSF [Cl-] and [HCO3-] in hypercapnia, suggesting that sodium-coupled chloride transport plays a role in regulation of CSF acid-base homeostasis.