Background: The SEMA3B protein plays an important role in suppressing tumor development as an angiogenesis inhibitor, which might be a predictable bio-marker for prognosis in hepatocellular carcinoma as our hypothesis. Methods: In this study, we have demonstrated the expression of semaphorin3B (SEMA3B) and microvascular density (MVD) in hepatocellular carcinoma (HCC) tissues. Results: We found that about 42.9% cells are SEMA3B-positive, which is significant lower compared with that of in normal liver and paraneoplastic tissues (78.6%, 85.7%, respectively). We observed that MVD in SEMA3B-positive HCC tumor tissues were lower than that of SEMA3B-negative (P<0.05). Our clinical data prospective study demonstrated that the lower expression of SEMA3B was closely related to the tumor nodular number, tumor size, capsulation and CLIP score (P<0.05) accordingly. As of rate of recurrence and metastasis, the patients in SEMA3B-positive group were significantly lower than that of the SEMA3B-negative group, also SEMA3B-positive group comes with the higher survival rate as well (P<0.05). Take them all together, we summarized that SEMA3B protein acts as an inhibitor though inhibiting angiogenesis, migration, and invasion during the process of human hepatocellular carcinoma. The downgraded expression level of SEMA3B closely associated with tumor progression and prognosis. Conclusion: SEMA3B could be an independent predictor of prognosis and a possible novel target of anti-angiogenic therapy for patients with HCC.