Homogenates of human skeletal muscle showed autolytic and cathepsin activity over a wide pH range with peaks at 3.6, 6.6 and 8.6. Some evidence was presented for the enzymatic and proteolytic nature of the autolytic process. Both myoglobin and hemoglobin were equally active as substrates at all pH peaks. In mildly abnormal muscle of patients with Duchenne muscular dystrophy, other dystrophies, dermatomyositis and neurogenic atrophies, both autolytic and cathepsin activity in the acid, neutral and alkaline range were either normal or slightly above normal. On the other hand, in severely degenerated muscles of patients with the same disease conditions, large increases in autolytic and cathepsin activity at all pH peaks were found. The increased activity of cathepsins was found to correlate with the degree of muscle degeneration. These results suggest that the cathepsins are involved in the muscle wasting process in human muscle diseases.