The effect of hyperoxia on cerebral blood flow (CBF) was examined in 12 unanesthetized ponies. CBF was determined using radioactive microspheres, 15 micrometer in diam, durijng inspriation of the following gases: 1) room air (control); 2) 40% I2 in N2; and 3) approximately 100% O2 with 2.2-4.5% CO2 added to maintain isocapnia. CBF did not change from control values during either level of hyperoxia. However, cerebrospinal fluid (CSF) carbon dioxide tension (PCO2) increased during 40% O2 (delta 1.0 Torr) and approximately 100% O2 (delta 2.9 Torr). This rise in CSF PCO2, not due to a change in CBF, may have resulted from a decrease in the CO2 carrying capacity of cerebral venous blood during hyperoxia (Haldane effect). Although respiration did not change during 40% O2, expired minute volume increased 25% during approximately 100% O2 due to an increase in tidal volume. This rise in respiration was not associated with changes in any of the conventional stimuli to breathing (arterial pH, O2 tension, or PCO2 or CSF pH). One possible explanation was that cerebral extracellular fluid pH, in the vicinity of the central chemoreceptors, or cerebral intracellular fluid pH changed in a direction unlike CSF pH. An alternate explanation was that the CO2 in the inspired gas activated CO2-sensitive receptors in the lungs.