Objectives: Induction of immunologic tolerance is the ultimate goal of organ transplant. To investigate the involvement of microRNA in tolerance induction after organ transplant, murine cardiac allografts were performed and the expression of microRNA in the grafts was analyzed. Materials and Methods: Cardiac allografts were performed using C57BL/10 (H2-Kb) to CBA/N (H2-Kk) fully mismatched combination with or without eicosapentaenoic acid for tolerance induction. Ten microRNA, mir-146a, 15b, 223, 23a, 27a, 34a, 451, 101a, 101b, 148a, discovered in hepatic grafts were examined by quantitative reverse transcription polymerase chain reaction using RNA from the cardiac allografts. Results: The administration of eicosapentaenoic acid markedly prolonged the cardiac allograft survival (median survival time > 100 days) and decreased the pathological score. Quantitative reverse transcription polymerase chain reaction revealed that mir-223 was up-regulated in accordance with pathological deterioration as compared with the expression observed in the syngeneic grafts. In contrast, the other microRNA was down-regulated. Pearson product moment correlation analysis demonstrated that the expression patterns of mir-223 and mir-146a had high or moderate positive associations between the cardiac and haptic allografts in mice. Conclusions:The change in the microRNA expression in the allografts suggests that microRNA plays a role in the induction and/or maintenance of tolerance after allograft transplant. Our findings suggest that mir-223 may be associated with rejection while mir-146a, -15b, -23a, -27a, -34a, -451, -101a, -101b, -148a may be involved in tolerance. A superior grasp of the mec hanism for rejection and tolerance observed in the murine heart allotransplant model may provide a better curative treatment strategy to mitigate allograft rejection.