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It has been reported that rapamycin (RPM) can induce de novo conversion of the conventional CD4 + Foxp3-T cells into CD4 + Foxp3 + regulatory T cells (iTregs) in transplantation setting. It is not clear whether RPM can similarly generate suppressor CD8 + T cells to facilitate graft acceptance. In this study, we investigated the ability of short-term RPM treatment in promoting long-term acceptance (LTA) of MHC-mismatched skin allografts by generating a CD8 + suppressor T-cell population. We found that CD4 knockout (KO) mice (in C57BL/6 background, H-2 b ) can promptly reject DBA/2 (H-2 d ) skin allografts with mean survival time (MST) being 13 days ( p < 0.01). However, a short course RPM treatment in these animals induced LTA with graft MST longer than 100 days. Adoptive transfer of CD8 + T cells from LTA group into recombination-activating gene 1 (Rag-1)-deficient mice provided donor-specific protection of DBA/2 skin grafts against cotransferred conventional CD8 + T cells. Functionally active immunoregulatory CD8 + T cells also resided in donor skin allografts. Eighteen percent of CD8 + suppressor T cells expressed CD28 as measured by flow cytometry, and produced reduced levels of IFN-γ, IL-2, and IL-10 in comparison to CD8 + effector T cells as measured by ELISA. It is unlikely that CD8 + suppressor T cells mediated graft protection via IL-10, as IL-10/Fc fusion protein impaired RPM-induced LTA in CD4 KO mice. Our data supported the notion that RPM-induced suppressor CD8 + T cells home to the allograft and exert donor-specific graft protection.