The neural cell adhesion molecule (N-CAM) is a cell-surface glycoprotein that may mediate some intercellular adhesive interactions in the nervous system. In adult rat muscle, N-CAM is concentrated near neuromuscular junctions and on satellite cells, but is nearly undetectable in nonsynaptic portions of myofibers. However, N-CAM is abundant throughout myofibers in denervated and regenerating muscles. Using affinity-purified antibodies to N-CAM, we were able to demonstrate a similar distribution and regulation of N-CAM in human muscle. Myofiber N-CAM was not detectable immunohistochemically in any of 10 normal biopsies or in 4 biopsies that were abnormal but showed no evidence of fiber denervation or regeneration. N-CAM was present, however, at end plates, nerves, and satellite cells in normal human muscle. In contrast, myofiber N-CAM was detected in 16 of 16 patients with histological evidence of denervation and in 10 of 10 patients who had myopathy with degenerating/regenerating myofibers. In addition, 2 of 2 histologically nondiagnostic biopsies from patients with amyotrophic lateral sclerosis contained N-CAM-positive myofibers. Immunoblot analysis also detected N-CAM in denervated and myopathic, but not normal, human muscle. These results suggest that N-CAM may play a role in muscle reinnervation or regeneration and that N-CAM immunohistochemistry may complement conventional techniques in the diagnosis of neuromuscular disease.