Sex differences in motor performance may arise depending on the mode of contraction being performed. In particular, contractions that are held for long durations, rather than contractions that are interspersed with rest periods, may induce greater levels of fatigue in men compared to women. The purpose of this study was to examine fatigue responses in a cohort of healthy men (n = 7, age [mean] = 21.6 ± [SD] 1.1 year) and women (n = 7, age: 22.0 ± 2.0 year) during sustained isometric and intermittent isometric contractions. Two contraction protocols were matched for intensity (20% MVC) and total contraction time (600-s). Biceps brachii EMG and elbow flexion torque steadiness were examined throughout each protocol, and motor nerve stimulation was used to quantify central and peripheral fatigue. Overall, there were few sex-related differences in the fatigue responses during intermittent contractions. However, men exhibited progressively lower maximal torque generation (39% versus 27% decrease), progressively greater muscle activity (220% versus 144% increase), progressively greater declines in elbow flexion steadiness (354% versus 285% decrease), and progressively greater self-perception of fatigue (Borg scale: 8.8 ± 1.2 versus 6.3 ± 1.1) throughout the sustained contractions. The mechanism underlying fatigue responses had a muscle component, as voluntary activation of the biceps brachii did not differ between sexes, but the amplitude of resting twitches decreased throughout the sustained contractions (m: 32%, w: 10% decrease). As generating large sustained forces causes a progressive increase in intramuscular pressure and mechanical occlusion—which has the effect of enhancing metabolite accumulation and peripheral fatigue—it is likely that the greater maximal strength of men contributed to their exacerbated levels of fatigue.