In human volunteers, lateral gastrocnemius muscles were stimulated electrically under ischemic conditions so as to produce fatigue. Recordings of electromyographic (EMG) activity were then made from those muscles and simultaneously from untreated medial gastrocnemius muscles during maximal voluntary efforts. In the lateral gastrocnemius the mean amount of EMG activity declined by 52% and was associated with a 35% reduction in the mean amplitude of the M wave (muscle compound action potential) and an insignificant change in M-wave area. In the medial gastrocnemius the EMG was also diminished, by 29%, but there were no significant changes in M-wave amplitude or area. The findings in the medial gastrocnemius are consistent with the existence of an inhibitory reflex effect which originates in the fatigued lateral gastrocnemius muscle and serves to depress excitation in motoneurons supplying that muscle and also in those innervating synergists. The inhibitory effect appears to be long-lasting, in that a significant reduction of the EMG could still be demonstrated 10 min after release of the arterial cuff.