The monoclonal antibodies anti-Leu-19 and anti-NKH-1 recognize the CD56 differentiation antigen expressed on natural killer (NK) cells and on a T-cell subset. Because CD56 is an isoform of neural cell adhesion molecule (N-CAM), we examined its expression on human muscle using antibodies to Leu-19, NKH-1, and purified N-CAM in an immunohistochemical, immunoblot, and immunoprecipitation study on 70 muscle biopsy specimens from various muscle diseases and on human muscle in tissue culture. Anti-Leu-19, anti-NKH-1, and anti-N-CAM had identical immunoreactive patterns. In tissue sections, they specifically recognized the satellite cells and the regenerating or newly denervated muscle fibers; in tissue cultures, they immunoreacted with myoblasts and myotubes; and in the homogenates of myopathic muscle and cultured myotubes, they immunoprecipitated the same glycoprotein of 145- to 220-kd. The study concludes that (1) the commercially available monoclonal antibodies to NK cells, Leu-19 and NKH-1, are immunocytochemical markers for the satellite cells and the regenerating or newly denervated muscle fibers complementing conventional techniques in the diagnosis of patients with neuromuscular disorders; and (2) the CD56 is a common antigen shared by NK cells and muscle fibers during certain stages of muscle maturation, regeneration, or denervation. When expressed in the muscle, CD56 may facilitate the adhesion of cytotoxic lymphocytes to the muscle and play a role in muscle fiber injury.