From our experimental results and what is known in the literature, we conclude that (1) sorafenib and 5-FU both possess antitumor activity in HCC cells; (2) compared with 5-FU monotherapy, combination treatment with sorafenib and 5-FU shows weaker effects when sorafenib is followed by 5-FU, while the effect is stronger when 5-FU is followed by sorafenib; and (3) sorafenib pretreatment reduces the sensitivity of HCC cells to 5-FU by down regulating cyclin D1 expression via inhibition of RAF/MEK/ERK and STAT3 signaling, which in turn results in G1-phase arrest and S-phase reduction. This evidence concerns the gene RAF1 and hepatocellular carcinoma.