Serological and immunopathological studies were carried out in five patients during and after repeated allogeneic and xenogeneic liver perfusions for hepatic coma. Patients received from 1 to 16 perfusions, each lasting 5–52 hr, using 24 livers obtained from four animal species and two human cadavers. All patients recovered consciousness; three survived for 1, 4, and 11 weeks, and two are alive and well 3 years after treatment. Before, and at intervals after treatment, patients' sera were examined for changes in the titer of preformed species-specific antibodies, cross reacting heterologous antibodies, the presence of heterologous serum proteins and antibody to these proteins, changes in the level of serum immunoglobulins and complement, and the development of antibodies to human transplantation antigens. Sections of the perfused livers and biopsies of patients' own livers and kidneys were examined histologically and by immunofluorescence. All perfusions were accompanied by rapid absorption of preformed heterologous antibody. After porcine liver perfusions, there followed a marked rise in the titer of species-specific antibodies, heterologous cross reacting antibodies, human anti-A and anti-B isoantibodies, and porcine serum protein antibody. Repeated baboon perfusion gave rise to only small elevations in the titer of heteroantibody but was not accompanied by clinical reactions and did not give rise to antibaboon serum protein antibody. Rising titer of cytotoxic antibody to human lymphocytes was observed in one patient who had also received blood and platelet transfusions. Examination of the perfused organs showed acute humoral xenograft rejection in all pig livers, but only mild or absent cell-mediated rejection in the baboon livers and in the human cadaver livers. Immunoglobulin deposition was not seen in patients' own livers or kidneys. These findings should have important implications in human heterotransplantation because they suggest that an accelerated liver homograft rejection may not occur when patients supported by hepatic perfusion subsequently receive orthotopie liver allografts.