Renal allograft survival may be prolonged indefinitely in some strains of rats following preoperative transfusion with whole blood from the organ donor. Similarly donor-specific transfusion results in a reduction in the proliferative response of lymph node (LN) white cells (WBCs) to donor-specific stimulators in mixed-lymphocyte culture (MLC). To determine the relative roles of major and minor histocompatibility antigens in the depression of the proliferative response, in vitro lymphocyte proliferation assays were performed using congenic rat strains as blood donors. Unidirectional MLCs were set up between haplotype-disparate responder and stimulator LN cells, in cases in which the responding cells had been harvested from rats transfused with blood that shared either some, all, or none of the major histocompatibility complex genes with the stimulator strain. The proliferative response of LN cells harvested from rats transfused with blood sharing major (class I or II) or minor antigens, or both, with the in vitro stimulator cells was significantly less than the response of cells harvested from nontransfused controls. No single-locus product was more or less effective than whole blood in depressing cell proliferation. These data suggest that the beneficial effect of preoperative random blood transfusions observed in clinical transplantation may arise from the fortuitous sharing by the blood donor and the subsequent organ donor of not only a single major histocompatibility antigen but also of minor histocompatibility antigens.