Thrombomodulin (TM) converts thrombin from procoagulant into anticoagulant protein to activate protein C. Thrombin also plays an important role in the metastatic process of cancer cells. We performed an immunohistochemical and clinicopathological study of TM in 141 cases with resected hepatocellular carcinoma (HCC) measuring less than 6 cm in diameter. Twenty-five specimens (17.73%) stained positive for TM. TM was found in the cytoplasm and surface of cancer cells. The clinicopathological findings according to the positive of TM are examined in HCC. The preoperative plasma TM level of the patients with tissue that stained positive for TM was significantly higher than that of the patients with negative results; for the postoperative TM level, there were no differences between them. In addition, the frequencies of intrahepatic metastasis, tumor thrombus in the portal vein, and capsular infiltration were significantly lower in patients whose tissue stained positive for TM than in patients whose tissue stained negative for TM. The recurrence freedom rate was significantly higher in patients whose tissue stained positive for TM than patients whose tissue stained negative for TM. Thus, TM-producing HCC shows a slow intrahepatic spread. Therefore, these findings suggest that TM may inhibit the adhesion of tumor cells to the portal vein because of anticoagulant activity and thus prevent the spread of intrahepatic metastasis.