In this study, we examined the effects of Flt3L in combination with Rapamycin in a BALB/c-to-C57BL/6 cardiac allograft model. Our results demonstrate that Flt3L combined with lowdose of Rapamycin prevented acute allograft rejection and prolonged allograft survival time. The enhanced allograft survival is associated with the induction of tolerogenic DCs along with the production of CD25 + Foxp3 + regulatory T cells and increased allograft autophagy. Our data suggest that Flt3L combined with low-dose of Rapa could be a promising therapeutic strategy in clinical transplantation.