The shortage of organs for transplantation is especially severe for the critically ill newborn infant, for whom donors of the appropriate size are particularly scarce. One way to overcome this problem is to use animals in lieu of humans as organ donors. The major limitation to using animals for this purpose is the susceptibility of animal organs to hyperacute rejection, a violent rejection reaction thought to be mediated by antidonor antibody and complement. To evaluate the potential application of xenotransplantation to newborns, we tested neonatal humans and neonatal baboons and found that neither population expressed significant levels of xenoreactive anti-pig antibodies. We transplanted heterotopically hearts from newborn pigs into unmanipulated newborn baboons (n = 4). There was no evidence of hyperacute rejection in any of the grafts; the animals were killed with functioning grafts at 15, 81, 82, and 82 hr. This outcome contrasts with that of newborn pig-to-mature baboon and mature pig-to-mature baboon cardiac xenografts, which were rejected within 1 hr of transplantation. The histology of pig graft biopsies from the newborn recipients was normal. Immunohistochemistry revealed only traces of IgM, C3, C4, and the membrane attack complex along graft endothelium. Fibrin deposition along endothelial surfaces was observed early after transplantation and became more extensive with time; in the absence of endothelial bound antibody or complement, this change may represent preservation injury. This study suggests that due to low levels of natural antibody, the newborn infant may permit prolonged xenograft survival.