T HE DEFENSE against homografts is presumed to be immunologic, vested in the reticuloendothelial system. It is logical, therefore, that the role of the lymph node in the rejection of peripheral tissue homografts should be undergoing investigation in several laboratories. We have been attempting to elucidate the rejection phenomenon, hoping to alter the host’s response to foreign tissue or to its code in the case of repeated confrontations by the same tissue. Scothorne and McGregor [l] first pointed out the increase in size and weight of the regional lymph node after transplantation of a skin homograft. Stark, Dwyer, and De Forest [Z] also found that the mass of lymph nodes increased markedly after homotransplantation, but changed little after autotransplantation or a sham operation. The lymph node desoxyribonucleic acid (DNA) : ribonucleic acid (RNA) ratio following homografting shows a rise in RNA, implying that antibodies were being formed within the nodes [3]. Mannick and coworkers [4] immunized lymph nodes in vitro by exposing them to RNA extracted from lymph nodes that had been immunized in viva. Mitchison [5] was able to transfer adoptive homograft immunity between animals by the homotransplantation of an immunized lymph node. We were able to enhance the life of homografts by subcutaneous injections of red blood cell hemolysate [6]. This was presumably due to an as yet unidentifiable enhancing factor, since blockading the node with the same material produced not enhancement but immunity. Radioactive chromium studies showed that the red cell substance acted at the lymph node locus. Surgical extirpation of the regional lymph nodes enhanced first and second set homografts. This was true in a human case in which bilateral male skin homografts were transplanted upon the upper arms of a woman who had undergone lymph node ablation as a part of radical mastectomy. Her surgical lymphedema was being treated by a Macey procedure to which the homograft challenge was added [Z]. Knox and co-workers [7J mitigated the violent and sudden end point of renal homograft by removal of the regional lymph nodes, even though they were dealing with vascular anastomosis which delivered antigen directly to the central reticuloendothelial system. In our control studies on rabbits, first set skin homografts upon the ears were rejected (50 per cent necrotic) on the fifty post-transplantation day, whereas second set grafts were rejected on the second day. In the following experiments, we have attempted to determine first, whether viability of the lymph node is essential for the typical homograft rejection; second, whether exclusion of cells from a viable node wouId minimize rejection and produce enhancement; third, whether homologous whole blood (containing enhancing substance) placed in a chamber with the regional node would exert an enhancing effect; and, fourth, whether second set homografts are destroyed by cell-bound or humoral antibodies.