Reductions in arterial O2 saturation (-5 to -10% SaO2 < rest) occur over time during sustained heavy intensity exercise in a normoxic environment, due primarily to the effects of acid pH and increased temperature on the position of the HbO2 dissociation curve. We prevented the desaturation via increased F1O2 (.23 to .29) and showed that exercise time to exhaustion was increased. We used supramaximal magnetic stimulation (1 - 100 Hz) of the femoral nerve to test for quadriceps fatigue. We used mildly hyperoxic inspirates (F1O2 .23 to .29) to prevent O2 desaturation. We then compared the amount of quadriceps fatigue incurred following cycling exercise at SaO2 98% vs. 91% with each trial carried out at equal exercise intensities (90% Max) and for equal durations. Preventing the normal exercise-induced O2 desaturation prevented about one-half the amount of exercise-induced quadriceps fatigue; plasma lactate and effort perception were also reduced. We conclude that the normal exercise-induced O2 desaturation during heavy intensity endurance exercise contributes significantly to exercise performance limitation in part because of its effect on locomotor muscle fatigue. These effects of EIAH were confirmed in mild environmental hypoxia (FIO2 .17, SaO2 88%) which significantly augmented the magnitude of exercise-induced quadriceps fatigue observed in normoxia.