The purpose of the present study was to compare the mechanisms of fatigue induced by a unilateral vs a bilateral submaximal isometric knee extension. Ten physically active men completed two experimental sessions, randomly presented. They were asked to maintain an isometric knee extension force corresponding to 20% of the maximal voluntary contraction (MVC) until task failure with one leg (unilateral) vs two legs (bilateral). MVCs were performed before and after the sustained contraction. Transcutaneous electrical stimuli were used to examine central (voluntary activation) and peripheral (peak doublet force at rest) fatigue on the exercised leg. Time to task failure was significantly shorter (P<0.05) for the bilateral (245 ± 76 s) compared with the unilateral task (295 ± 85 s). Unilateral MVC force and maximal voluntary activation losses were significantly greater (P<0.05) after the unilateral task than after the bilateral task. Peak doublet force was significantly reduced (P<0.01) after the unilateral task, but not after the bilateral task. The present results demonstrated that time to task failure of a submaximal fatiguing contraction may depend on the number of limbs involved in the task. The greater time to task failure with one leg may have induced greater contractile alterations and a larger MVC loss following the unilateral task.