Objective:To investigate the expression and clinical significance of ADP-ribosylation factor 6(ARF6) in hepatocellular carcinoma (HCC). Methods:The expression of ARF6 was determined by tissue microarray and immunohistochemistry in 150 cases of HCC and 48 cases of adjacent cirrhosis tissue. Results:The positive expression of ARF6 in HCC and adjacent cirrhosis tissue were 48.7% (73/150) and 8.3% (4/48) respectively(P < 0.05). The positive expression of ARF6 in HCC was closely related to the portal vein invasion,clinical stage,tumor diameter and AFP level. The results also indicated that a high expression level of ARF6 was associated with worse recurrence-free survival. The median recurrence-free survival was substantially reduced among patients with positive ARF6 protein(36 months vs. 45 months,P = 0.019 1). Conclusion:The expression of ARF6 is closely correlated with the clinical prognosis of HCC. It suggests ARF6 may be a potential prognostic biomarker and therapeutic target for HCC.