Immobilization of the rabbit knee in extension has previously been shown to damage the vastus intermedius profundus (VIP) muscle. To examine the mechanism of the early stages of the muscle damage, the authors studied creatine kinase activity in serum, and both light and electron microscopic changes in the affected muscle. The right knee was immobilized in an extended position using a splint, and thigh muscles were removed at various intervals, up to 48 hours after immobilization. The left hindlimb served as a control. Creatine kinase levels in serum rose ten hours after the onset of the immobilization. The enzyme levels reached a substantial peak by 24 hours, and plateaued thereafter. Light microscopic changes were not observed within 48 hours, but in electron microscopy distinct mitochondrial swelling and crystal abnormalities were seen as early as ten hours. The ultrastructural changes of mitochondria remained constant for up to 36 hours and decreased thereafter. At 48 hours of immobilization, also myofibrillar disorganization was seen. It appears that immobilization of the rabbit knee in extension rapidly leads to signs of remarkable damage to the VIP muscle. These suggest leakage of the cell membrane and metabolic disturbances. The ultrastructural changes observed share common features with muscle damage caused by ischemia, uncoupling agents, and inherited mitochondrial myopathies.