Objective: To investigate the expression of cell division cycle 6 (CDC6) in hepatocellular carcinoma (HCC) and its clinical significance. Methods: The mRNA and protein expressions of CDC6 in 85 surgical specimens of HCC tissue and matched adjacent tissue were determined by qRT-PCR, Western blot analysis and immunohistochemical staining, respectively. The relations of CDC6 expression with clinicopathologic characteristics and prognosis of HCC patients were analyzed. Results: Both mRNA and protein expression levels of CDC6 were increased in HCC tissue compared with adjacent tissue, and quantitative analysis of qRT-PCR results showed that the difference had statistical significance (P<0.05). The CDC6 expression was significantly related to tumor size, clinical stage, degree of differentiation and satellite lesions (all P<0.05). Both tumor-free survival rate and overall survival rate in patients with high CDC6 expression were significantly lower than those in patients with low CDC6 expression (both P<0.05), and both univariate and multivariate analyses showed that CDC6 was an independently risk factor for tumor-free survival rate (HR=1.089, 95% CI=0.986–1.186, P=0.033) and overall survival rate (HR=2.441, 95% CI=1.128–3.652, P=0.012) in HCC patients. Conclusion: CDC6 is highly expressed in HCC tissue, and is closely related to malignant clinicopathologic features and poor prognosis. CDC6 may contribute to the occurrence and development of HCC, and may be used as an index for estimating tumor recurrence and outcomes.