A model of chronic renal rejection in the Dark-Agouti to Albino-Surgery rat combination is described. In a number of cases, the original allograft was replaced by a second Dark-Agouti allograft. Seventy-five percent of rats experienced early episodes of rejection that subsided spontaneously. Second allografts had better initial renal function. Variable degrees of tubular atrophy, interstitial fibrosis, vascular damage, glomerulosclerosis, deposition of humoral mediators, and mononuclear leukocyte infiltrate were observed in all long-term allografts. Chronic damage increased with time, and was less severe in second allografts. At 5 days, total interstitial infiltrate was similar to that seen in unmodified rejection, but there was a significant increase in CD4+ cells and a decrease in ED2 and IL-2R expression. Subsequently, the total interstitial infiltrate decreased with time, although it remained significantly higher than in isografts and residual kidneys from uninephrectomized rats. No significant decrease over time was seen in numbers of CD4+ and CD45RC+ cells. The latter had a marked focal distribution after 100 days. Total leukocyte infiltrate was similar in original and second allografts, but there were changes in the proportions of leukocyte subpopulations, including significantly lower numbers of CD45RC+ cells in the latter. The persistence of CD45RC+ cells throughout the course of chronic rejection and their lower numbers in the second allografts favors a role for these cells in the development of chronic injury. The model of chronic renal allograft rejection characterized in this study will be valuable in further studies of the mechanisms of injury in this pathology.