Objective: To investigate the inhibitory effect of quercetin on the growth of hepatocellular carcinoma (HCC) cells in vivo and the mechanism. Methods: Tumor xenograft model was established by subcutaneous inoculation of human HCC HepG2 cells into the nude mice. After tumor formation, the tumor-bearing mice were randomly divided into control group, quercetin treatment group, 5-FU treatment group, and quercetin plus 5-FU combination treatment group, and the vehicle or drugs were administered by intraperitoneal injection once daily. At three weeks after treatment, the tumor size in each group was observed and the tumor inhibition rate in each treatment group was calculated, and the expressions of cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in the xenograft tumor tissues were determined by RT-PCR, Western blot and immunohistochemical staining, respectively. Results: Compared with control group, the tumor size was reduced, and the mRNA and protein expressions of cyclin D1 and cyclin E as well as PCNA positive index in tumor tissue were decreased significantly in each treatment group (all P<0.05), where the tumor inhibition rate in combination treatment group was significantly greater, and the decreasing degrees in expressions of cyclin D1, cyclin E and PCNA were all significantly larger than that in either of the single agent treatment group (all P<0.05), but all the parameters between the two single agent treatment groups showed no significant difference (all P>0.05). Conclusion: Quercetin can inhibit the proliferation of HCC cells by down-regulating cyclin D1 and cyclin E expressions, and may exert a synergistic action in combination with 5-FU.