Objective: To investigate the expression and significance of intermediate-conductance calcium-activated potassium channel protein 4 (SK4) in hepatocellular carcinoma (HCC). Methods: The surgical specimens of HCC and adjacent tissues from 46 HCC patients were collected. The expressions of SK4 and vascular endothelial growth factor (VEGF) in the two types of tissues were measured by immunohistochemical staining, and the correlation between SK4 and VEGF expression was analyzed. The SK4 mRNA expressions in the two types of tissues were determined by real-time PCR, and the relations of SK4 mRNA expression with the clinicopathologic factors were analyzed. The SK4 protein expressions in the two types of tissues were detected by Western blot analysis. Results: The results of immunohistochemical staining showed that the positive expression rates of both SK4 and VEGF in HCC tissue were significantly higher than those in adjacent tissue (both P<0.05), and there was a positive correlation between SK4 and VEGF expression in HCC tissue (r=0.364, P<0.05). The results of real-time PCR showed that SK4 mRNA expression in HCC tissue was significantly up-regulated compared with adjacent tissue (P<0.05), and the high SK4 mRNA expression was associated with poor differentiation and portal vein tumor thrombus (both P<0.05). The results of Western blot showed that the SK4 protein expression level in the cell membrane of cells from HCC tissue was significantly higher than that of cells from adjacent tissue, but the expression levels in the cytoplasm of both tissues had no obvious difference between them. Conclusion: The SK4 expression is increased in HCC, which may promote the invasion and metastasis of HCC through up-regulating VEGF expression or others.