Introduction: Cardiac lymphatics are essential in resolving interstitial fluid and inflammatory infiltrate after a myocardial infarction in adults. Little is known about the role of the lymphatic system during neonatal cardiac regeneration following injury in the perinatal animal with an immature lymphatic system. Hypothesis: Our hypothesis is that TIE1, an endothelial specific receptor tyrosine kinase essential for lymphatic development in mice, is required for myocardial repair following infarction (MI) in both neonatal and adult mice. Methods: Using an inducible and lymphatic specific deletion model, Prox1Cre-ER T2 ;Tie1 fl/fl , both mutant and non-mutant control mice undergo myocardial MI with left anterior descending coronary ligation. Adult surgery is performed at 6-8 weeks of age. Conditional Tie1 deletion is induced by ingestion of tamoxifen enriched chow 48 hours prior to adult ligation and continued until dissection is performed; cardiac function is assessed throughout this time by echocardiogram. Neonatal surgery is performed at postnatal day 2 (P2) and conditional Tie1 deletion induced with intraperitoneal tamoxifen with functional assessment by echocardiogram at P4 and P21. Results: Adult control animals had a robust lymphangiogenic response within the scar infarct border zone at 6 weeks post-MI that was not seen in mutants at 6 weeks. Furthermore, Tie1 deletion following led to a an increase in maximal injury, severe depression of cardiac function, and a blunted myocardial repair response, noted by histological analysis of the scar area. Similarly, Tie1deletion in the neonatal period resulted in markedly attenuated regenerative response with persistent scar function at P21. Conclusions: Lymphatic expression of Tie1 in the adult is required for myocardial repair following injury. In addition, lymphatic expression of Tie1 is required for optimal myocardial regeneration in the neonate even though the cardiac lymphatic system is immature in the postnatal period. Further delineation of the mechanisms involved in Tie1 mediated repair and regeneration may provide novel opportunities for therapeutic intervention following cardiac injury in both neonates and adults.