SUMMARY In an investigation of the genesis of the perivascular mononuclear cell infiltrates and subsequent tissue damage in unmodified renal allograft rejection using cyclophosphamide-treated and bone marrowgrafted rats and parental strain to F1 hybrid transplants, it is shown that: (1) it is the interaction of donor and recipient genetically dissimilar hematopoietic cell lines, in part donor-organ lymphocytes, that generates the proliferative reaction of the cortical interstitium; (2) abrogation of this proliferative reaction significantly prevents the vascular and tubular injury of the graft in unsensitized recipients and, to a lesser extent, in sensitized recipients. These experiments suggest that the important immunogens in rejection are of hematopoietic origin and are not necessarily the parenchymal or endothelial cells of the organ allotransplant