Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal PCO 2 (PETCO 2) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W peak). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which PETCO 2 was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower PETCO 2 (40 Torr) from ∼75 to 100% W peak to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping PETCO 2 at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping PETCO 2 at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (∼40%) and improved cerebral hemoglobin oxygenation (∼15%), but decreased W peak (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (∼15%), but again limited W peak (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO 2-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis. Copyright © 2011 the American Physiological Society.