This study evaluated whether the reduction of prefrontal cortex oxygenation (ScO₂) during maximal exercise depends on the hyperventilation-induced hypocapnic attenuation of middle cerebral artery blood velocity (MCA V_mean). Twelve endurance-trained males (age: 25 ± 3 years, height: 183 ± 8 cm, weight: 75 ± 9 kg; mean ± SD) performed in three separate laboratory visits, a maximal oxygen uptake (VO₂max) test, an isocapnic (end-tidal CO₂ tension (PetCO₂) clamped at 40 ± 1 mmHg), and an ambient air controlled-pace constant load high-intensity ergometer cycling to exhaustion, while MCA V_mean (transcranial Doppler ultrasound) and ScO₂ (near-infrared spectroscopy) were determined. Duration of exercise (12 min 25 s ± 1 min 18 s) was matched by performing the isocapnic trial first. Pulmonary VO₂ was 90 ± 6% versus 93 ± 5% of the maximal value (P =.012) and PetCO₂ 40 ± 1 versus 34 ± 4 mmHg (P <.05) during the isocapnic and control trials, respectively. During the isocapnic trial MCA V_mean increased by 16 ± 13% until clamping was applied and continued to increase (by 14 ± 28%; P =.017) until the end of exercise, while there was no significant change during the control trial (P =.071). In contrast, ScO₂ decreased similarly in both trials (−3.2 ± 5.1% and −4.1 ± 9.6%; P <.001, isocapnic and control, respectively) at exhaustion. The reduction in prefrontal cortex oxygenation during maximal exercise does not depend solely on lowered cerebral blood flow as indicated by middle cerebral blood velocity.