Objective: To investigate the domain containing 7A (THSD7A) expression in human hepatocellular carcinoma (HCC) and its clinical significance. Methods: The THSD7A mRNA expression in 30 fresh specimens of HCC with paired and adjacent tissues, and protein expression in 75 paraffin embedded specimens of HCC with paired adjacent tissues were detected by RT-PCR and immunohistochemical staining, respectively. The relations of THSD7A protein expression with clinicopathologic parameters and prognosis of HCC patients were analyzed. Results: The THSD7A mRNA expression in HCC tissue was significantly down-regulated compared with adjacent tissue (P<0.05), and the positive expression rate of THSD7A protein in HCC tissue was significantly lower than that in adjacent tissue (24.0% vs. 87.0%, P<0.05). The THSD7A protein expression was significantly related to the tumor numbers (P=0.011), Edmondson-Steiner grade (P=0.013) and BCLC stage (P=0.048) of the patients. Both overall survival and disease-free survival in patients with low THSD7A expression were significantly lower than those in patients with high THSD7A expression (P=0.016, P=0.013). Conclusion: THSD7A may play a tumor-suppressor role in HCC, and those with decreased THSD7A expression have a relatively poor prognosis.