OBJECTIVE To determine normal acid-base status of the CSF and to compare it with changes during acute hypercapnia in equine neonates. METHODS 10 clinically normal foals between 1 and 12 days old. METHODS CSF and arterial and venous blood samples were collected every 15 minutes during 45 minutes of normocapnia and 90 minutes of hypercapnia in isoflurane-anesthetized foals. CSF samples were collected via a subarachnoid catheter placed in the atlanto-occipital space. RESULTS Comparison of blood and CSF gases during normocapnia indicated that CSF was significantly more acidic than blood. The lower pH was attributable to higher CO2 and lower bicarbonate concentrations than those in blood. During hypercapnia, CSF CO2 increased and pH decreased parallel to changes in blood, but changes were not a great as similar changes in venous blood, indicating that some degree of buffering occurs in the CSF of foals. CONCLUSIONS Normal CSF acid-base status in equine neonates is similar to that in other domestic species. The blood-brain and blood-CSF interfaces in neonates allow rapid diffusion of CO2, but allow only slow diffusion of bicarbonate. Equine neonates are capable of buffering respiratory-induced acid-base changes in the CSF, but the buffering capacity is less than that of the vascular compartment. CONCLUSIONS Neonatal foals may develop severe respiratory compromise, resulting in hypoxemia and hypercapnia. Because the ability of the CSF to buffer acid-base changes in neonates is reduced, hypercapnia may contribute to the CNS abnormalities that often develop in sick neonates. Thus, normal blood gas values should be maintained in diseased equine neonates.