Changing arterial oxygen content (C(aO(2))) has a highly sensitive influence on the rate of peripheral locomotor muscle fatigue development. We examined the effects of C(aO(2)) on exercise performance and its interaction with peripheral quadriceps fatigue. Eight trained males performed four 5 km cycling time trials (power output voluntarily adjustable) at four levels of C(aO(2)) (17.6-24.4 ml O(2) dl(-1)), induced by variations in inspired O(2) fraction (0.15-1.0). Peripheral quadriceps fatigue was assessed via changes in force output pre- versus post-exercise in response to supra-maximal magnetic femoral nerve stimulation (DeltaQ(tw); 1-100 Hz). Central neural drive during the time trials was estimated via quadriceps electromyogram. Increased C(aO(2)) from hypoxia to hyperoxia resulted in parallel increases in central neural output (43%) and power output (30%) during cycling and improved time trial performance (12%); however, the magnitude of DeltaQ(tw) (-33 to -35%) induced by the exercise was not different among the four time trials (P > 0.2). These effects of C(aO(2)) on time trial performance and DeltaQ(tw) were reproducible (coefficient of variation = 1-6%) over repeated trials at each F(IO(2)) on separate days. In the same subjects, changing C(aO(2)) also affected performance time to exhaustion at a fixed work rate, but similarly there was no effect of Delta C(aO(2)) on peripheral fatigue. Based on these results, we hypothesize that the effect of C(aO(2)) on locomotor muscle power output and exercise performance time is determined to a significant extent by the regulation of central motor output to the working muscle in order that peripheral muscle fatigue does not exceed a critical threshold.