In the present study, we found that the expression of FNDC5 was elevated in sorafenib-resistant cells and that drug-resistant cells with high expression of FNDC5 were not sensitive to treatment with sorafenib, whereas FNDC5-knockdown HCC cells were readily killed by sorafenib as observed using the EdU and CCK8 assays. Here, FNDC5 is linked to hepatocellular carcinoma.