A sustained voluntary contraction increases central fatigue and produces a 'cross-over' of fatigue during a subsequent contraction of the contralateral limb. These studies compared the magnitude of these changes for men and women. Force and electromyographic responses from dominant (study 1; n=8 men, 8 women) or non-dominant (study 2; n=7 men, 8 women) leg extensors to nerve stimulation were recorded at rest and during brief maximal voluntary contractions (MVCs), before and after 100-s sustained MVCs performed with the dominant leg. For the dominant leg, force was reduced more for men (by similar to 24%) than women (by similar to 16%, P < 0.05) after the sustained contractions. Similarly, voluntary activation during these contractions was reduced more for men (by similar to 22%) than women (by similar to 9%, P < 0.05). Conversely, resting twitches changed similarly for both sexes (P > 0.05). For the non-dominant leg, men experienced a reduction in force (by 1 similar to 3%, P < 0.001) and had greater deficits in activation than women (similar to 9% vs similar to 3%, P < 0.05), after sustained contractions of the dominant leg. Therefore, sustained MVCs produce greater central fatigue and a more pronounced 'cross-over' of effects to the contralateral limb for men compared to women. These findings demonstrate distinct differences between sexes in the way the nervous system adapts to changes associated with fatigue.