In addition to transplant-associated vascular sclerosis, cardiac allografts also may be vulnerable to a previously unrecognized aspect of remodeling involving reactivation of fetal structural genes in the adult heart. Vascular smooth muscle (VSM) alpha-actin is encoded by a gene that normally is repressed in the ventricle during late gestation. Immunohistochemical analysis of accepted mouse cardiac allografts was performed to determine whether this fetal actin was reexpressed after transplant. VSM alpha-actin was detected within 30 days after transplant throughout the allograft myocardium, where it frequently exhibited a distinct periodicity suggestive of protein localization in sarcomeres. By 90 days after transplant, VSM alpha-actin filaments specifically accumulated in the left ventricular endocardium. Donor hearts and isografts did not express myocardial VSM alpha-actin, indicating that fetal gene activation was linked to chronic rejection. The results indicate that chronic rejection is associated with fetal muscle gene activation, which may facilitate parenchymal cell remodeling and impair graft function.