SUMMARYA long-term study of the fate of parabiotic hamsters differing at weak histocompatibility loci is presented. Animals were evaluated on the bases of gross appearance, survival time, weekly weight changes, and autopsy studies. One outbred and several partially inbred strains were employed. The course of chronic and subacute parabiotic rejection is detailed. Diverse manifestations of reticulo-endothelial response were noted. These included developing liver “microabscesses,” lymphoid atrophy and hyperplasia, proliferation of plasma cells, and marked splenic hematopoiesis. Two varieties of amyloidotic change occurred in intermediate and long-surviving partners. The various findings are discussed in relation to transplantation immunology, experimental amyloidosis, and an immunologic theory of aging. The following tentative conclusions are set forth: (1) the hamster has few strong but probably many weak histocompatibility antigens; (2) chronic and subacute parabiotic reactions between partners differing only at weak loci are manifestations of transplantation disease; (3) hamsters may remain in parabiosis for prolonged periods and with continuous exchange of cells without becoming tolerant of each other—in fact, a continuous, waxing and waning, often subclinical, immunologic battle takes place between the partners; (4) amyloidosis may be produced experimentally in the hamster by transplantation immune mechanisms; (5) the production of such disease in young animals by such a mechanism is consistent with theoretical expectations of the immunologic theory of aging; and (6) reactions involving weak histocompatibility antigens may reveal not only quantitative but actual qualitative differences from studies concerned chiefly with strong histocompatibility antigens.