Infants with fatal cardiac disease often die awaiting transplantation because of the shortage of donor hearts. The Hospital for Sick Children (HSC), Toronto, Canada, has researched and applied the concept of crossing the blood group compatibility barrier. Heart transplantation at HSC unrestricted by ABO compatibility greatly contributed to decreasing the mortality rate among infants on the waiting list from 58% to 10%. From January 1996 to January 2002, 16 infants less than 14 months of age received ABO-incompatible heart transplants at our institution. The cardiopulmonary bypass (CPB) circuit is primed with additional volume to replace the patient's blood volume. Packed red blood cells (PRBC) used in priming must be ABO-compatible with the recipient. All plasma components and platelets must contain no anti-A or anti-B antibodies to donor or recipient. CPB is initiated and the patient's venous blood is collected into a transfusion bag and sent to the blood bank. The total amount collected should be one and a half to two times the patient's blood volume. The plasma is separated and discarded, returning only the PRBC, thus reducing the concentration of circulating antibodies to blood group antigens. Our team has experienced an 87% survival rate with this technique. The success is believed to be associated with the recipients' immunologic immaturity. Newborns do not produce isohemagglutinins, and serum anti-A and anti-B antibody titers usually remain low until 12-14 months of age. The complement system is not fully developed, therefore, the mediators of hyperacute rejection are absent during early infancy. Heart transplantation unrestricted by the need for ABO compatibility would effectively expand the available donor pool and decrease waiting times.