The main findings of the current study are the following: (1) compared with healthy control, CHB, and LC, serum zonulin was significantly increased in HCC; (2) higher levels of zonulin were correlated with advanced stage of LC and HCC; and (3) zonulin was more reliable diagnostic biomarker than the traditional marker AFP in differentiating between LC and HCC. Here, AFP is linked to hepatocellular carcinoma.