This study compared the time to task failure for a submaximal fatiguing contraction in the presence and absence of a cognitive stressor in men and women. In study 1, 10 men and 10 women (22 ± 3 yr of age) performed an isometric fatiguing contraction at 20% maximal voluntary contraction force until task failure with the elbow flexor muscles during two separate sessions. Subjects performed a mental-math task during one of the fatiguing contractions that aimed to increase anxiety and stress (stressor session). Salivary cortisol and reported levels of arousal (visual analog scale for anxiety, and State-Trait Anxiety Inventory scores) were elevated during the stressor session compared with a control session for both sexes (P < 0.05). Time to task failure, however, was briefer during the stressor session compared with control (P = 0.005) but more so for the women (27.3 ± 20.1%) than the men (8.6 ± 23.1%) (P = 0.03). The briefer time to task failure was associated with target force (r2 = 0.21) and accompanied by a higher mean arterial pressure, heart rate, and rate-pressure product during the fatiguing contraction in the stressor session compared with control in women. In study 2 (11 men and 8 women, 20 ± 3 yr of age), time to task failure was similar for a fatiguing contraction with simple mental-math that did not increase stress (mental-attentiveness session) and control for both men and women. The greater change in fatigability of women than men with performance of a cognitive stressor involved initial strength and increases in indexes of sympathetic neural activity and cardiac work compared with control conditions.