Objective To establish a mouse model of acute antibody-mediated rejection (AMR) in heart transplantation and to analyze its characteristics. Methods Mouse models of heart transplantation and skin transplantation were established. According to different treatment methods, all animals were divided into the homologous control group, non-sensitized group, pre-sensitized group and pre-sensitized+ ciclosporin group (9 donors and 9 recipients in each group). The graft survival time, donor-specific antibody (DSA) level and pathological manifestations of each group were observed, and the characteristics of rejection were analyzed. Results In the homologous control group, the cardiac grafts of the mice survived for a long period of time during the 3-month observation period. The survival time of the cardiac grafts in the non-sensitized group, pre-sensitized group and pre-sensitized+ciclosporin group was (7.0±0.7) d, (2.6±0.5) d and (5.0±0.7) d, respectively. The differences among the groups were statistically significant (all P < 0.01). The DSA level in the pre-sensitized group was significantly elevated than the baseline level at 3 d after heart transplantation, and that in the pre-sensitized+ciclosporin group was remarkably up-regulated at 5 d after heart transplantation, the differences were statistically significant (P < 0.05, P < 0.01). The pathological manifestation of the non-sensitized group was the myocardial cell destruction, the formation of interstitial inflammation, mild C4d deposition and a large amount of CD3 cell infiltration. The pathological manifestations of the pre-sensitized group and the pre-sensitized+ciclosporin group showed myocardial cell destruction, capillary inflammation and a large amount of C4d deposition, whereas the amount of CD3 cell infiltration in the pre-sensitized group was more than that in the pre-sensitized+ciclosporin group. Conclusions The use of ciclosporin on the basis of heart transplantation and skin transplantation between different strains of mice can successfully establish a practical acute AMR model in mouse heart transplantation, which provides the basis for subsequent AMR pathogenesis and intervention research.