Objective To explore the expression of serum protein induced by vitamin K absence or antago⁃ nist ⁃Ⅱ（PIVKA ⁃Ⅱ）in advanced hepatocellular carcinoma（HCC）and its relationship with clinicopathological characteristics and prognosis. Methods Chemiluminescence method was used to detect serum PIVKA⁃Ⅱ and AFP levels in105 patients with advanced HCC，93 patients with benign hepatic diseases，and 90 healthy volunteers； survival analysis was performed by Kaplan ⁃Meier method and Log ⁃ rank test；univariate and multivariate analysis were performed using the Cox proportional hazard analysis；the receiver operating characteristic（ROC）curve was used to analyze the efficacy of serum PIVKA⁃Ⅱ and AFP in diagnosing of advanced HCC. Results The expression levels of PIVKA⁃Ⅱ and AFP in advanced HCC group were significantly higher than those in benign hepatic diseases and control group（P < 0.05）；the high⁃expression of PIVKA⁃Ⅱ in advanced HCC patients were correlated with the tumor size，tumor number，vascular invasion and TNM stag（P < 0.05）；the 5⁃year OS and PFS in low⁃expres⁃ sion group were significantly better than those in high ⁃expression group（P < 0.05）；PIVKA ⁃Ⅱ high ⁃expression was independent risk factors affecting 5⁃year OS and PFS in advanced HCC patients（P < 0.05）；the AUC of the combined detection of the two in the diagnosis of HCC is significantly higher than that of single detection（P < 0.05）. Conclusion PIVKA⁃Ⅱ was up⁃regulated in advanced HCC patients and its high⁃expression was closely related with several unfavorable clinicopathological features and prognosis，and it might be an important biomarker for predicting the prognosis of advanced HCC.