In this study, we tried to find a reliable biomarker of HCC, and serum exo‐miR‐4661‐5p was identified as an effective biomarker for HCC at all stages, including early stage, with a greater degree of accuracy than serum AFP (AUROC of serum exo‐miR‐4661‐5p = 0.923 vs AUROC of serum AFP = 0.541, P < .0001). This evidence concerns the gene AFP and hepatocellular carcinoma.