Objective: To investigate the expression of interferon-induced transmembrane protein 3 (IFITM3) in hepatocellular carcinoma (HCC) and its significance. Methods: Fifty-five specimens of paired HCC and adjacent tissues were collected, in which the IFITM3 protein expressions were determined by immunohistochemical staining and Western blot analysis, respectively, and the relations of IFITM3 expression with the clinicopathologic factors of HCC patients were also analyzed. After transfection with interfering sequences against IFITM3, the changes in invasion and migration ability in HCC HepG2 cells were observed. Results: Results of immunohistochemical staining showed that the IFITM3 positive expression rate in HCC tissue was significantly higher than that in its adjacent tissue (88.2% vs. 23.5%, P<0.05), and in low/moderate differentiated HCC tissue was significantly higher than that in high differentiated HCC tissue (80.0% vs. 8.3%, P<0.05); results of Western blot analysis demonstrated that IFITM3 protein expression level in HCC tissue was significantly higher than that in its adjacent tissue (1.2 399 vs. 0.9 565, P<0.05); IFITM3 expression level was significantly associated with portal vein tumor thrombosis, tumor size and TNM stage (all P<0.05). Both invasion and migration abilities in HepG2 cells were remarkably reduced after transfection with interfering sequences against IFITM3. Conclusion: IFITM3 expression is increased in HCC, and its increasing degree is closely associated with invasion and migration ability of HCC cells, which suggest that IFITM3 plays an important role in the process of malignant progression in HCC.