Immunocytochemical analysis of muscle specimens from 5 patients with acute quadriplegic myopathy indictes that depletion of either fast or slow myosin occurs in this disorder. The initial lesion consists of focal myosin loss in nonatrophic fibers. Other structural proteins (actin, titin, nebulin) are spared or affected only at an advanced stage of the disease. Attempts at regeneration, evidenced by expression of fetal myosin and desmin, occur in some fibers. Calpain expression is markedly enhanced in the affected fibers, implicating an altered calcium homeostasis in the evolution of the pathologic process. By contrast, cathepsin B and ubiquitin expressions are only minimally affected. The history of 1 of our patients indicates that severe systemic illness in and of itself can cause acute quadriplegic myopathy.