Antibody-mediated rejection (ABMR) has been become the most important barrier to long-term graft survival in the modern solid organ transplantation. However, lack of good mouse models for ABMR makes it difficult to develop effective strategies to overcome ABMR. This study aimed to establish ABMR models in murine heart transplantation using human HLA A2-transgenic (TG) mice. Tail skins of HLA-A2-TG mice were transplanted onto the back of wild-type (WT) B6 mice and hearts of the HLA-A2-TG mice were transplanted into the sensitized B6 mice 3 weeks after sensitization. Serum titers of anti-HLA A2 antibodies were serially measured using ELISA. Heart graft survival was monitoring by palpation. Deposition of immunoglobulin and complement component 4d (C4d) was measured using immunohistochemistry. HLA-A2- TG mice showed significant level of expression in endothelial cells, hearts, kidneys, tail skins, and the spleens. Anti-HLA-A2 IgG titer in the serum was increased by 7-fold compared to the baseline value after sensitization by skin transplantation and moreover increased up to 500-fold by subsequent heart transplantation. WT B6 heart grafts to sensitized B6 mice achieved long-term graft survival without rejection, while HLA A2-TG heart grafts to sensitized B6 mice ceased to beat at median of 5 days. Addition of conventional maintenance immunosuppressants such prednisolone, tacrolimus, and sirolimus significantly decreased anti-HLA-A2 antibody titer and increased HLA-A2-TG heart graft survival in sensitized mice. In HLA-A2-TG grafts, there was significant vasculitis with myocarditis together with infiltration of CD3+ T cells and CD68+ macrophages, which were markedly decreased by combination. Both IgG and C4d were also deposited in endothelial cells in capillary or artery in HLA-A2-TG grafts. Using HLA-A2-TG heart transplantation to sensitized B6 mice, we successfully established murine models of ABMR by anti-MHC antibodies and hope this model could provide platform to develop new strategies to overcome ABMR in organ transplantation.