To clarify the organ specific nature of hyperacute rejection, 14 puppies were presensitized by multiple skin grafts and spleen cell injections prior to receiving either a heart or kidney allograft from the respective donors. Of this group, 7 received orthotopic heart allografts and 7 received kidney allografts. All heart allografts were rejected between 3 and 28 hours, and all kidneys between 0 and 24 hours as judged by cessation of urine flow from the ureterostomies. In contrast, all 11 animals in a recent series of heart allografts in non-sensitized puppies survived the operation, and rejected between 7 and 17 days. There was a significant correlation in both groups between preoperative cytotoxic antibody titer in the recipient serum and graft survival time. The preoperative titers were all above 1:1,024 but were greatly reduced within 2 hours after transplantation. At the time of rejection, antibody could be eluted from the rejected organs. In contrast to the kidneys, in which 2 of 7 grafts ceased to function immediately after revascularization, all hearts resumed beating and functioned well for at least several hours. At autopsy, the myocardium was pale and edematous and histologically polymorphonuclear leukocytes were prevalent in and around the small vessels and among myofibers. Both IgG and IgM antibody was detected in sarcolemma of the myocardium and to a lesser extent in the intima and adventitia of the small vessels by the fluorescent antibody technique. Biopsies of the rejected kidneys showed polymorphonuclear leukocyte infiltration, typical of hyperacute rejection. Marked fluorescence of IgG and IgM in the glomeruli and peritubular capillaries was observed. This study indicates that both organs rejected hyperacutely in our experimental model and participation of the preformed antibody in effecting this change was strongly suggested.