What is the central question of this study? How does acute hypoxia alter central and peripheral fatigue during brief and sustained maximal voluntary muscle contractions? What is the main finding and its importance? Perception of fatigue during muscle contractions was increased progressively for 2 h after hypoxic exposure. However, an increase in motor cortex excitability and a decrease in voluntary activation of skeletal muscle were observed across the entire protocol when performing brief (3 s) maximal contractions. These adaptations were abolished if the brief contraction was held for a duration of 20 s, which was presumably attributable to a successful redistribution of blood to overcome the reduced oxygen content. Few studies have examined the time course of changes in the motor system after acute exposure to hypoxia. Thus, the purpose of this study was to examine how acute hypoxia affects corticospinal excitability, voluntary activation (VA) and the perception of fatigue during brief (3s) and sustained (20s) maximal voluntary contractions (MVCs). Fourteen healthy individuals (23±2.2years of age; four female) were exposed to hypoxia and sham conditions. During hypoxia, peripheral blood oxygen saturation was titrated over a 15min period and remained at 80% during testing. Corticospinal excitability and VA were assessed before titration (Pre), 0, 1 and 2 h after. At each time point, the brief and sustained elbow flexion MVCs were performed. Motor evoked potentials (MEPs) were obtained using transcranial magnetic stimulation. Superimposed and resting twitches were obtained from motor point stimulation of biceps brachii to calculate the level of VA, and ratings of perceived fatigue were obtained with a modified CR-10 Borg scale. A condition-by-time interaction was detected for the CR-10 Borg scale, whereby perception of fatigue increased progressively throughout the hypoxia protocol. However, main effects of MEP area and VA indicated that corticospinal excitability increased, and VA of the biceps brachii decreased, throughout the hypoxia protocol. Given that these changes in MEP area and VA were seen only when performing the brief MVCs (and not during the sustained MVCs), performing longer contractions might overcome reduced oxygen content by redirecting blood flow to active areas of the motor system.