Inbred miniature swine that are treated for 12 d with a high dose of cyclosporin A develop tolerance to MHC class II matched, class I-mismatched renal allografts. The aim of this study was to clarify the intrarenal allograft events associated with the development of tolerance in this protocol. Morphologic and immunologic studies were performed in serial biopsies from accepting grafts after 12 d of cyclosporin A treatment (n = 4) and were compared with those from untreated control rejecting grafts (n = 4). In accepting grafts with stable function, a transient interstitial infiltrate developed. The cellular infiltrate had many similarities to that in rejecting grafts; both had T cells and macrophages, similar proportions of T-cell subsets, and a similar frequency of in situ nick end labeling (TUNEL)+ apoptotic infiltrating cells. However, the cellular infiltrate in the acceptance reaction was distinguished by less T-cell activation (interleukin-2 receptor+), less proliferation (proliferating cell nuclear antigen+) of infiltrating cells, and less graft cell apoptosis in arteries, tubules, glomeruli, and peritubular capillaries. Thereafter, the infiltrate in the accepting grafts progressively resolved with decreased cell proliferation, activation, and apoptotic graft parenchymal cell injury, but the high frequency of apoptosis persisted in graft-infiltrating cells. In parallel to the intragraft events, donor-specific unresponsiveness developed as assessed by cell-mediated cytotoxicity by blood mononuclear cells in vitro. In conclusion, the acceptance reaction in transplanted grafts is characterized by progressive resolution of T-cell proliferation and activation and of cell-mediated graft injury, as well as prolonged T-cell apoptosis. These intragraft events suggest that both T-cell anergy and T-cell deletion occur in the graft during the development of tolerance. Some of the described immunopathologic findings (activation, proliferation, apoptosis) may be useful in distinguishing acceptance from rejection, as well as in predicting later graft acceptance in tolerance induction protocols.