Hepatocellular carcinoma is a common malignancy of digestive system. Tumor markers are important for the early diagnosis and prognosis of hepatocellular carcinoma. Protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) is of high specificity and sensitivity in hepatocellular carcinoma diagnosis. In addition, previous studies suggested that PIVKA-Ⅱ played a role in proliferation, invasion and metastasis of hepatocellular carcinoma and could be used for prognosis of hepatocellular carcinoma. This article reviewed the recent advances in the underlying biological mechanism of PIVKA-Ⅱ in hepatocellular carcinoma and concluded the value of PIVKA-Ⅱ in hepatocellular carcinoma diagnosis and prognosis.