Myocardial infarction, myocardial scar tissue formation, and cardiac arrhythmogenesis seem to be associated. There are electrophysiological data suggesting that myocardial nerves are involved in arrhythmia development; however, there are no morphologic studies describing the fate of these nerves following necrotizing myocardial injuries. To describe the reactions of Schwann cells and axons following such injuries, we induced lesions in rat hearts with ischemia or transdiaphragmatic freeze-thawing and examined the acutely necrotic, healing, and healed lesions with light and electron microscopy. Antibodies to Schwann cell-associated S-100 protein were used to facilitate histologic detection. Both forms of injury produced focal lesions in which Schwann cells were killed and axonal segments destroyed; however, the basal lamina sheaths of cardiac myocytes and capillaries, and probably also of nerve fibers, remained largely intact. During 4 weeks of sequential observations, Schwann cells and axons were components of a hypercellular healing front that began at the periphery and moved toward the center of each lesion. Their proliferation and growth may have occurred within the original nerve basal lamina sheaths, and reparative axonal enlargements contained an abundance of 50- to 100-nm clear and dense storage granules. Fully developed nerve fibers were not only present in newly formed scar tissue but also appeared to be present in significantly greater density than in uninjured myocardial tissue. These findings demonstrate that proliferative nerve fiber regeneration occurs from the edges of necrotizing myocardial injuries, that healing results in relatively large number of nerve fibers in newly formed scars, and that axons in these scar-associated nerve fibers contain an abundance of neurosecretory granules. The functional significance of these observations remains to be determined.