Reductions in prefrontal oxygenation near maximal exertion may limit exercise performance by impairing executive functions that influence the decision to stop exercising; however, whether deoxygenation also occurs in motor regions that more directly affect central motor drive is unknown. Multichannel near-infrared spectroscopy was used to compare changes in prefrontal, premotor, and motor cortices during exhaustive exercise. Twenty-three subjects performed two sequential, incremental cycle tests (25 W/min ramp) during acute hypoxia [79 Torr inspired PO2 (PIO2)] and normoxia (117 Torr PI O2) in an environmental chamber. Test order was balanced, and subjects were blinded to chamber pressure. In normoxia, bilateral prefrontal oxygenation was maintained during low- and moderate-intensity exercise but dropped 9.0 ± 10.7% (mean ± SD, P < 0.05) before exhaustion (maximal power = 305 ± 52 W). The pattern and magnitude of deoxygenation were similar in prefrontal, premotor, and motor regions (R2 > 0.94). In hypoxia, prefrontal oxygenation was reduced 11.1 ± 14.3% at rest (P < 0.01) and fell another 26.5 ± 19.5% (P < 0.01) at exhaustion (maximal power = 256 ± 38 W, P < 0.01). Correlations between regions were high (R2 > 0.61), but deoxygenation was greater in prefrontal than premotor and motor regions (P < 0.05). Prefrontal, premotor, and motor cortex deoxygenation during high-intensity exercise may contribute to an integrative decision to stop exercise. The accelerated rate of cortical deoxygenation in hypoxia may hasten this effect. Copyright © 2009 the American Physiological Society.