【Abstract】 Objective To investigate the diagnostic value of protein induced by vitamin K deficiency or antagonist-Ⅱ protein induced by vitamin K deficiency or antagonist-Ⅱ (PIVKA-Ⅱ)in HCC. Methods From December 2016 to December 2017, 154 patients (HCC group), 126 patients with liver cirrhosis (cirrhosis group) and 153 patients with stomach and colon cancer (stomach and colon cancer group) initially diagnosed as HCC in the Affiliated Hospital of Southwest Medical University were selected for retrospective analysis. Serum PIVKA-Ⅱ and AFP levels were measured. The detection efficiency of PIVKA-Ⅱ and AFP were analyzed by the working characteristic curve of subjects. The sensitivity and specificity of the two groups were compared. Results The levels of PIVKA Ⅱ and AFP in HCC group were significantly higher than those in cirrhosis group, gastric cancer group and colon cancer group (P＜0.001). There was a significant difference in AFP level between the cirrhosis group and the stomach and colon cancer group (P＜0.001). There was no significant difference in PIVKA-Ⅱ between the two groups (P＞0.05). In HCC group, the level of PIVKA-Ⅱ increased with the increase of tumor diameter (P＜0.001). According to the comparison of portal vein thrombosis and distant metastasis, it was found that the levels of PIVKA-Ⅱ and AFP were higher in patients with portal vein thrombosis and distant metastasis (P＜0.01). According to the clinical stages of liver cancer in Barcelona, the differences of PIVKA-Ⅱ and AFP in different periods were statistically significant (P＜0.01). Spearman's rank correlation analysis showed that there was no correlation between the expression of PIVKA-Ⅱ and AFP in HCC group (P＞0.05). In the group of stage D liver cancer, the Spearman correlation coefficient of the two indexes was correlated (P＜0.01). In the cirrhosis group, the ROC AUC detected by PIVKA-Ⅱ alone, PIVKA-Ⅱ and AFP jointly was significantly higher than that detected by AFP alone (P＜0.001). The threshold values of PIVKA-Ⅱ and AFP were determined by yoden index. The sensitivity of PIVKA-Ⅱ single detection was higher than that of AFP single detection and combined detection (P＜0.05). There was no significant difference in the specificity between PIVKA-Ⅱ and combined detection (P＞0.05). Conclusion The detection efficiency of serum PIVKA-Ⅱ is better than that of AFP. It can be used in the diagnosis of HCC and has high clinical application value.