Cytohesin-2 is overexpressed in human lung cancer and it activates cytoplasmic ErbB receptors. Inhibition of cytohesin-2 by SecinH3 reduces growth of EGFR-dependent lung cancer xenografts and improves the treatment of primarily EGFR-TKI-resistant lung cancers. Cytohesin-2 promotes HepG2 proliferation through the IGF pathway, and VEGF-dependent initiation of angiogenesis by regulation of VEGFR-2 internalization in endothelial cells, vessel permeability and ultimately endothelial proliferation. The purpose of this study was to evaluate the effects of cytohesin-2 in hepatocellular carcinoma (HCC). In the current study, we collected 40 HCC tissues and detected cytohesin-2 mRNA expression in the 40 HCC tissues by using quantitative real-time polymerase chain reaction (qRT-PCR), as well as its protein expression by using immunohistochemistry and western blot analysis. We found that cytohesin-2 was more highly expressed in HCC compared to adjacent non-tumorous liver tissues, and cytohesin-2 expression was significantly increased in specimens with high α-fetoprotein and vascular invasion. Both univariate and multivariate analyses indicated that there is an association between cytohesin-2 expression and overall survival (OS) and disease-free survival (DFS). Moreover, stratified analysis showed that patients in tumor-node-metastasis (TNM) stage I with higher cytohesin-2 levels had shorter OS and DFS than those with lower cytohesin-2 levels. In conclusion, cytohesin-2 may identify low-and high-risk individuals with HCC and may be a valuable indicator for stratifying prognosis of TNM stage I patients. Cytohesin-2 may serve as a novel prognostic biomarker for HCC.