Objective To compare the impact of the sirolimus and tacrolimus on the tumor recurrence after liver transplantation due to HCC beyond Milan criteria.Method Sixty-one liver transplantation recipients due to HCC beyond Milan criteria,between Jan.2008 and Apri.2012,were randomized,with the informed consent,into two different immunosuppression groups: sirolimus group (n=30) and tacrolimus group (n=31).In tacrolimus group,tacrolimus was used as the basic immunosuppressant,methylprednisolone was discontinued within one month postoperatively,and mycophenolate mofetil was used within the dosage of 1.5 g/d accordingly.In sirolimus group,the immunosuppresive scheme was the same as that of the tacrolimus group within postoperative one month,and from that,tacrolimus was transferred to sirolimus.No antineoplastic agents were given before tumor recurrence.The tumor recurrence rate and the survival rate of the recipients were compared between the two groups.Result The median follow-up duration was 35.2 months (10.3～ 60.2).The tumor recurrence rate at postoperative year 1,2,3 and 4 in the sirolimus group (13.3％,36.7％,43.3％ and 53.3％) was significantly lower than that in the tacrolimus group (38.7％,67.7％,74.2％ and 77.4％),P ＜ 0.05 for all.The one-year survival rate in the recipients postoperation had no significant difference between sirolimus group and tacrolimus group (90.0％ vs.87.1％,P=0.438).The 2-,3-and 4-year survival rate in the recipients was significantly higher in the sirolimus group (53.3％,33.3％ and 20.0％) than that in the tacrolimus group (41.9％,22.6％ and 9.7％),P ＜ 0.05 for all.The liver function and renal function of the recipients at the postoperative year 1,2,3 and 4 showed no significant difference between the two groups,P＞0.05.Conclusion In comparison with tacrolimus,sirolimus could significantly reduce the tumor recurrence rate and increase the survival rate for the liver transplant recipients due to HCC beyond Milan criteria.