Objective To investigate the effect of sirolimus (SRL)-based immunosuppression regimen on the survival and tumor recurrence in liver transplantation recipients with hepatocellular carcinoma beyond the standard Milan criteria. Methods We retrospectively analyzed 22 patients who received liver transplant in our hospital for HCC beyond the standard Milan criteria from June 2010 to June 2011. Eleven patients received tacrolimus for immunosuppression after liver transplant and the other 11 were converted from tacrolimus to SRL-based immunosuppression. The incidence rate of acute rejection, tumor-free survival period, blood routine, liver function and complications were compared between the two groups. Results The incidence rates of acute rejection were not significantly different between the two groups after a mean follow-up of (12±3) months (range, 7-18 months). Four patients in the SRL group and eight patients in tacrolimus group had HCC recurrence and metastasis. Kaplan-Meier recurrence-free survival curves demonstrated that SRL group had a significantly longer HCC recurrence-free survival than tacrolimus group(P<0.05). Compared with tacrolimus group, SRL group had significantly lower leukocyte and platelet counts (P<0.05). The tacrolimus-related nephrotoxicity was modestly improved in all the three patients after converted to SRL. Two patients suffered oral ulcers after conversion to SRL treatment and no severe complications such as arterial thrombosis were observed. ConclusionSRL can be effectively used for liver transplant recipients with hepatocellular carcinoma beyond the standard Milan criteria; it can achieve a similar anti-rejection effect to tacrolimus and can greatly reduce tumor recurrence.