We studied the effect of changes in inspired [O2] on partial pressure of CO2 in arterial blood (PaCO2) during treadmill exercise (3 mph, 3% grade) in normal, acute (+2-4 wk), and chronic (+1-2 yr) carotid body-denervated (CBD) ponies. In all studies, PaCO2 decreased (P less than 0.01) from rest during exercise, reaching a nadir usually between 15 and 30 s of exercise. During normoxia [partial pressure of O2 in arterial blood (PaO2) approximately 95 Torr], the PaCO2 nadir was 2.3 +/- 0.6 Torr below resting level in normal ponies, but the nadir was greater (P less than -0.01) in acute (delta = 6.4 +/- 0.8 Torr) and chronic (delta = -4.7 +/- 1.1 Torr) CBD ponies. Hyperoxia (PaO2 approximately 180 Torr) accentuated (P less than 0.01) the hypocapnia only in the normal ponies (delta = -6.3 +/- 1.0 Torr). In contrast, hypoxia (PaO2 48 Torr) attenuated (P less than 0.01) the exercise-induced hypocapnia by 3-5 Torr in all ponies. Usually PaCO2 gradually increased after 30 s of exercise, reaching a stable level 1-3 Torr below rest by about 2 min (P less than 0.05). Tidal volume (VT) increased from rest during the first 15 s of exercise only when there was a large decrease in PaCO2. Recovery of PaCO2 after 30 s of exercise was associated with a decrease in VT toward rest. We concluded the following. 1) The accentuated hypocapnia caused by eliminating (CBD) or reducing (hyperoxia) carotid chemoreceptor activity suggests that the chemoreceptors normally dampen alveolar ventilation (VA) at the onset of exercise. 2) Attenuation of the hypocapnia at the onset of exercise by hypoxia in CBD ponies suggests that a direct CNS effect of hypoxia dampens VA. 3) Mechanisms tending to minimize the hypocapnia during exercise appear to adjust VA by modulating VT.