Objective: To investigate the association of Tspan8 expression with metastatic potential and prognosis in hepatocellular carcinoma (HCC). Methods: The mRNA and protein expressions in different HCC cell lines and surgical specimens of 80 HCC patients were determined by qRT-PCR and Western blot analysis, and Tspan8 expressions in tissue samples from another 352 HCC patients were detected by tissue microarray. The relations of Tspan8 expression with clinicopathologic factors as well as recurrence and prognosis in HCC patients were analyzed. Results: Both mRNA and protein expressions of Tspan8 were significantly higher in HCC cell lines with high metastatic potential (MHCC97-H, MHCC97-L) than those in HCC cell lines with low metastatic potential (PLC/PRF/5, SMMC7721, HepG2), significantly higher in HCC tissue than those in tumor-adjacent tissue or normal liver tissue, and significantly higher in HCC tissue from patients with intrahepatic metastases or vascular invasion than those in HCC tissue from patients without intrahepatic metastases and vascular invasion (all P<0.05). High Tspan8 expression was independent risk factor for postoperative recurrence (HR=1.64, 95% CI=1.21–2.23, P=0.002) and survival (HR=1.66, 95% CI=1.23–2.25, P=0.001), and in patients with high Tspan8 expression compared with those with low Tspan8 expression, the postoperative 5-year overall survival was signi?cantly decreased and time to tumor recurrence was significantly shortened (both P<0.05). Conclusion: Tspan8 can promote HCC metastasis and invasion, and patients with high Tspan8 may face a poor prognosis.