Fatigue of tibialis anterior (TA) was induced by repetitive electrical stimulation. Using this test, patients with upper motor neuron muscle weakness owing to multiple sclerosis (MS) and injuries to the spinal cord showed greater fatigability of their TA muscles, suggesting that the muscle fiber population changed toward that typical of fatigable motor units. During repetitive stimulation, in addition to the decrement in tension there was an increase in half-relaxation time of tetanic contractions at 40 Hz in both subjects and patients. The increase in half relaxation during repeated activity was greater in patients with MS and spinal cord injury than in healthy subjects, suggesting that the long-term inactivity affected the efficiency of the Ca2+ uptake mechanism of their muscle fibers. Thus long-term inactivity of patients with upper motoneuron dysfunction leads to increased fatigability of their muscles and exaggerates the slowing of muscle relaxation after prolonged exercise.