The chemokine receptor CCR9 was recently implicated in tumor biology. In the present study, our objective was to evaluate the clinical significance and potential role of CCR9 in hepatocellular carcinoma (HCC). CCR9 expression was detected by immunohistochemistry, quantitative PCR (qPCR) and western blotting in HCC patients. The prognostic significance of CCR9 expression was assessed. The functional roles of CCR9 in HCC were investigated using MTT, BrdU, colony formation assay and flow cytometry. CCR9 was significantly elevated in HCC tissue samples. High CCR9 expression was correlated with multiple tumor nodes, high Edmondson-Steiner grade and vascular invasion. Multivariate analysis showed that CCR9 expression was an independent prognostic factor for the overall survival (OS) of HCC patients. Further investigations revealed that ectopic expression of CCR9 enhanced cell proliferation and tumorigenicity in HCC cells, whereas CCR9 silencing impaired cell proliferation and tumorigenicity, which was mediated through downregulation of the cell cycle regulators p21, p27 as well as upregulation of cyclin D1. These results suggest that CCR9 can act as a novel prognostic marker and therapeutic target for HCC.