*Purpose: After liver transplantation (LT), immunosuppression is needed to avoid rejection and graft loss, however, it can stimulate hepatocellular carcinoma (HCC) recurrence and progression. Previous studies have shown that metformin had an anticancer effect on several cancers, including HCC. The aim of this study was to evaluate the interactions between metformin and immunosuppressive agents including sirolimus, tacrolimus and mycophenolate mofetil (MMF) for antitumor activity.

*Methods: Three cell lines (Huh7, HepG2 and Hep3b) were tested. Cell viability was determined using a MTT assay and Western blot analysis for mammalian target of rapamycin (mTOR) pathway related proteins were performed to reveal their mechanism.

*Results: Metformin and sirolimus had synergistic antiproliferative effect and sirolimus plus metformin supplemented with MMF also showed synergistic antiproliferative effect in specific HCC cells. Synergistic effect of metformin and sirolimus through the inhibition of mTOR and its down-stream, p70S6K, and p-4EBP1 were demonstrated. Metformin and sirolimus also showed synergistic effect for the down-regulation of Livin and Survivin expressions in HepG2 and Hep3b cells. In conclusion, metformin had synergistic interactions with sirolimus in terms of anticancer effects for HCC cells and the mechanism explaining this synergistic inhibition might be related with mTOR pathway.

*Conclusions: These results may provide a foundation for further studies for patients with HCC who underwent LT in clinical era.

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