Background: Numbers of patients with extrahepatic metastasis of hepatocellular carcinoma (HCC) are increasing. As characteristics of HCC patients who develop distant metastasis remain uncertain, we analyzed potential risk factors. Methods: Among patients followed up after hepatic resection for HCC, we identified 31 patients with extrahepatic metastasis (extrahepatic metastasis group, EM). In 46 other patients we found intrahepatic metastasis synchronously with the primary HCC. In these patients no extrahepatic metastasis occurred during 5 years of follow-up (intrahepatic metastasis group, IM). During the 5-year follow-up period, 14 patients have remained alive with no metastasis (no metastasis group, NM). We compared age, gender, hepatitis virus infection status, grade of liver dysfunction, serum alpha-fetoprotein (AFP) concentration, tumor size, tumor differentiation, presence of portal or hepatic venous infiltration, and surgical strategy among these three groups. Results: No significant difference in clinicopathologic factors was noted among the three groups except for immunohistochemical staining for CD44. A significantly higher proportion of tumors was immunoreactive for CD44v3 in the EM group than in the other groups ( [Formula: see text] ). By multivariate analysis, CD44v3 expression (risk ratio, 9.28; [Formula: see text] ) was a significant independent risk factor for extrahepatic metastasis. Conclusion: CD44v3 expression in HCC may be a useful predictor of likelihood of distant metastasis.