Eccentric exercise induces muscle damage and delayed-onset muscle soreness that peaks 24–48 h after the exercise. However, little is known about the effect of damaged muscle on muscle fatigue and the central nervous system, which interact with one another. PURPOSE: This study examined how the muscle damage induced by repetitive eccentric exercise with maximal voluntary effort (ECC) affects the time course of central and peripheral fatigue during sustained maximal voluntary contraction (MVC). METHODS: Ten healthy male volunteers were asked to perform brief (control MVC) and sustained (fatigue test of 60 s in duration) MVC with elbow flexion before and 2 and 4 d after ECC. In addition, another ten healthy male volunteers were asked to perform these tasks before and after injection of isotonic saline (0.9%, 1.0 ml, ISO) or hypertonic saline (5.25%, 1.0 ml, HYP) into the left biceps brachii. During the fatigue test, transcranial magnetic stimulation (TMS) of the motor cortex was used to determine the changes in voluntary activation (VA), size of the motor evoked potential (MEP), and length of electromyographic (EMG) silencing. The ratio of the root mean square value for the surface EMG of the biceps brachii and force exerted within 50 ms before TMS was also calculated (RMS/F). RESULTS: Control MVC was significantly decreased and muscle soreness was significantly increased, 2 and 4 d after ECC in comparison with that before ECC (P <0.001). During the fatigue test, VA, which was determined as a phasic increase in the twitch force after TMS, decreased significantly 2 and 4 d after ECC in comparison with that beforehand (P <0.01). In addition, the RMS/F was significantly increased 2 and 4 d after ECC (P <0.001). Although the degree of facilitation of the MEP was increased significantly (P <0.05), the length of EMG silencing was less affected by ECC. However, during the fatigue test, there was no significant difference in these parameters between HYP and ISO (P > 0.05). CONCLUSIONS: The muscle damage induced by repetitive eccentric exercise with maximal effort, and not delayed-onset muscle soreness, may be a strong modifier of central and peripheral fatigue during sustained MVC.