Unanesthetized ponies were given 4% CO2 (inspired CO2 pressure = 28 Torr) to breathe at two levels of arterial O2 pressure (PaO2): 1) near 75 Torr and 2) near 200 Torr. During 4% CO2 breathing, at either level of PaO2, the mean arterial CO2 pressure (PaCO2) was unchanged from control measurements (control measurements were made at the same PaO2, but with no CO2 in inspired air), suggesting that awake ponies can "clear" 4% CO2. The ability of individual ponies to clear 4% CO2 was quite variable: some ponies did not clear 4% CO2 and others cleared 4% CO2 on one day but not on the following day. Based on the average of 20 experiments, however, PaCO2 was unchanged from 40 Torr during inspiration of 4% CO2. Direct measurement of chemical stimuli to breathing in arterial blood and cisternal cerebrospinal fluid indicate that ventilation increased during CO2 breathing even though PaCO2, pHa, PaO2, and CSF pH were not changed in a direction that might explain the accompanying change in ventilation. The authors suggest that stimuli to receptors other than peripheral or medullary chemoreceptors may be responsible for the reported "isocapnic hyperpnea."