Previous studies on pathophysiological mechanisms of chronic graft rejection demonstrated the impact of both alloresponsiveness and nonspecific immunological events on the process. To study the role of alloantigen-specific factors further, we hypothesized an acceleration of chronic graft rejection after presensitization. Chronically rejected renal allografts in the established Fischer 344 → Lewis rat model were replaced sequentially by native allografts of donor origin. Grafting of second allografts was performed 2, 4, 8, and 12 weeks after the original transplantation and followed long term. Second allografts demonstrated significantly ameliorated functional and structural alterations with few cellular infiltrates. These changes were independent from the time interval between first and second engraftment (2-12 weeks); immunosuppressive treatment after the second engraftment was not influential. The nonresponsiveness was not restricted to the second kidney allografts, as heart allografts of donor origin in these recipients also functioned indefinitely, whereas third-party grafts (Lewis × Brown Norway F1) and Fischer 344 heart grafts in untreated Lewis control rats were acutely rejected.Thus, donor-specific and tissue-nonspecific graft acceptance is achieved by second engraftment of donor-specific allografts in a model of chronic graft rejection. Those observations demonstrate the synergistic effects of alloresponsiveness and of the injured graft itself for the development of chronic graft failure.