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The current standard of care for neonates with hypoplastic left heart syndrome (HLHS) includes a series of cardiac operations culminating in a complete cavopulmonary connection. Given the increased workload placed on the right ventricle, development of ventricular dysfunction and heart failure are concerns. As this patient population ages, many may require cardiac transplantation. Cellbased strategies to treat heart failure in adults have been reported, but little is known about their feasibility and efficacy in children with congenital heart disease. In an effort to attenuate or prevent the progression of heart failure that leads to the need for cardiac transplantation, we have developed an autologous cell-based protocol for infants with HLHS. We present the first reported case of direct intramyocardial injection of umbilical-cord blood–derived mononuclear cells in an infant with HLHS undergoing stage-II surgical palliation.