We aimed to determine whether post-exercise depression of motor-evoked potentials (MEP) could be demonstrated without voluntary muscle activation in humans. Voluntary fatigue was induced with a 2-minute maximal voluntary contraction (MVC) of the first dorsal interosseous muscle (FDI). On another occasion, "electrical fatigue" was induced with trains of shocks delivered for 2 minutes over the FDI motor point. Five of the 12 subjects also underwent "sequential fatigue" consisting of a 2-minute MVC of FDI followed by 20 minutes of rest then 2 minutes of motor point stimulation. Voluntary fatigue induced MEP depression that persisted for at least 20 minutes. Electrical fatigue induced a transient MEP facilitation that subsided 20 minutes after the stimulation and became depressed within 30 minutes. Thus, MEP depression can be induced by both voluntary and electrical fatigue. With electrical fatigue, the initial depression is "masked" by transient MEP facilitation reflecting cortical plasticity induced by the prolonged electrical stimulation. MEP depression probably reflects tonic afferent input from the exercising muscle that alters cortical excitability without altering spinal excitability.