Chronic rejection is the most important cause of graft failure after the first year of transplantation. In addition to the effects of host immunological injury, antigen-independent factors may gain in importance over the long term. We therefore assessed the influence of such factors on rat kidney isografts functioning for prolonged periods and compared our findings with those observed in naive control rats and in allograft recipients. Functional, morphological, and immunohistological changes in the isografts became obvious 32 weeks after engraftment, and by 52 weeks the findings mimicked those of chronic allograft rejection. As allografted kidneys sustained these changes earlier on and more intensely, both alloantigen-independent and -dependent factors are thought to be implicated in this process.