We examined the effects of hypoxia severity on peripheral versus central determinants of exercise performance. Eight cyclists performed constant-load exercise to exhaustion at various fractions of inspired O2 fraction (FIO2 0.21/0.15/0.10). At task failure (pedal frequency < 70% target) arterial hypoxaemia was surreptitiously reversed via acute O2 supplementation (FIO2= 0.30) and subjects were encouraged to continue exercising. Peripheral fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) as measured pre- versus post-exercise in response to supramaximal femoral nerve stimulation. At task failure in normoxia (haemoglobin saturation (SpO2) ∼94%, 656 ± 82 s) and moderate hypoxia (SpO2∼82%, 278 ± 16 s), hyperoxygenation had no significant effect on prolonging endurance time. However, following task failure in severe hypoxia (SpO2∼67%; 125 ± 6 s), hyperoxygenation elicited a significant prolongation of time to exhaustion (171 ± 61%). The magnitude of ΔQtw,pot at exhaustion was not different among the three trials (−35% to −36%, P= 0.8). Furthermore, quadriceps integrated EMG, blood lactate, heart rate, and effort perceptions all rose significantly throughout exercise, and to a similar extent at exhaustion following hyperoxygenation at all levels of arterial oxygenation. Since hyperoxygenation prolonged exercise time only in severe hypoxia, we repeated this trial and assessed peripheral fatigue following task failure prior to hyperoxygenation (125 ± 6 s). Although Qtw,pot was reduced from pre-exercise baseline (−23%; P < 0.01), peripheral fatigue was substantially less (P < 0.01) than that observed at task failure in normoxia and moderate hypoxia. We conclude that across the range of normoxia to severe hypoxia, the major determinants of central motor output and exercise performance switches from a predominantly peripheral origin of fatigue to a hypoxia-sensitive central component of fatigue, probably involving brain hypoxic effects on effort perception.