By performing a head-to-head comparison of the four diagnostic markers of HCC for the first time, the present study demonstrated that AFP remained the best single marker, and the combined use of AFP with PIVKA-II or DKK-1 had the best diagnostic performance (with a sum of Sn and Sp > 1.5) compared to all other possible combinations of the four biomarkers, even in early stage HCC. Here, AFP is linked to hepatocellular carcinoma.