Selective lymphoid irradiation (SLI) with palladium-109-hematoporphyrin (Pd-H) combined with antilym-phocyte globulin (ALG) induces either donor-specific permanent rat heart allograft acceptance or significant allograft prolongation depending on the degree of donor-recipient matching. The purpose of this study was to determine if SLI combined with ALG can affect ACI heart allograft survival in Lewis recipients presensitized to ACI, and of hamster heart xenografts in Lewis rats. Lewis rats were presensitized by three successive ACI skin allografts, 10 days apart; all had elevated induced anti-ACI cytotoxic antibodies prior to treatment. Each experiment included untreated control animals, animals treated daily with ALG (5 mg) alone for 2 days before cardiac grafting, and recipients treated with 28 mc of Pd-H per kg 4 days before cardiac grafting and ALG as above. In group 1 the ACI heart allograft was done 14 days after the third skin allograft, while in group 2 it was done 34 days after the last skin allograft. Anti-ACI antibody titer was 1 to 2 dilutions lower in animals in group 2 than in group 1. Group 3 consisted of Lewis recipients of hamster hearts and all had preformed antihamster lymphocytotoxic antibodies. SLI combined with ALG delays allograft and xenograft rejection in the presence of induced or preformed anti-donor antibodies, and converts primarily a humoral rejection into a cellular rejection by mechanisms as yet uncertain. Such peritransplant treatment had significant effect on the levels of antidonor complement-dependent cytotoxic antibody titers but did not correlate directly with graft survival. Histological analysis of rejected hearts in all groups demonstrated primarily a humoral hyperacute rejection in control animals and in recipients treated with ALG alone, while peritransplant treatment with Pd-H and ALG resulted not only in prolonged graft survival but histologically, primarily a cellular rejection of the graft.