A short course of procarbazine hydrochloride (PCH; 50 mg/kg) and antilymphocyte serum (ALS; 5 ml/kg), administered to Lewis (LEW;RT11) rats in the first week following transplantation of Brown Norway (BN;RT1n) kidneys, substantially prolonged allograft survival and induced long-term survival in 62% of the grafts. The two agents acted synergistically, in that neither of them administered alone had much effect. Graft recipients did not produce detectable cytotoxic antibodies and antigen-reactive cells injected i.v. were not diverted to the liver, thus showing that neither antibodies nor immune complexes are likely to mediate the unresponsiveness. Spleen cells from graft-bearing recipients failed to cause graft-versus-host responses (GVHR) in both (LEWxBN)F1 and (LEWxDA)F1 hybrids, but they specifically suppressed the GVHR given by normal syngeneic cells to donor strain (BN) antigens. This suppression was specific because the response against third-party antigens (DA; RTIa) was unaffected. Adoptive transfer of spleen and thymus cells from PCH-ALS-treated LEW rats bearing healthy BN kidneys caused a profound prolongation of BN graft survival in sublethally irradiated LEW recipients. This transfer was specific and mediated by W3/13+ (T) lymphocytes. It is concluded that a limited regimen of PCH and ALS given in the first postoperative week incites the generation of specific suppressor T lymphocytes and that this form of immunosuppression, even without preoperative donor antigen, is an effective way of prolonging kidney allograft survival.