A mass spectrometry-based methodology has been developed to study changes in core-fucosylation of serum ceruloplasmin that are site-specific between cirrhosis and hepatocellular carcinoma (HCC). The serum samples studied for these changes were from patients affected by cirrhosis or HCC with different etiologies, including alcohol, hepatitis B virus or hepatitis C virus. The methods involved trypsin digestion of the ceruloplasmin into peptides followed by Endo F3 digestion which removed most of the glycan structure while retaining the innermost N-acetylglucosamine (GlcNAc) and/or core-fucose bound to the peptide. This procedure simplified the structures for further analysis by mass spectrometry where 4 core-fucosylated sites (sites 138, 358, 397 and 762) were detected in ceruloplasmin. The core-fucosylation ratio of 3 of these sites increased significantly in alcohol-related HCC samples (sample size=24) compared to alcohol-related cirrhosis samples (sample size=18), with the highest AUC value of 0.838 at site 138. When combining the core-fucosylation ratio of site 138 in ceruloplasmin and the AFP (alpha-fetoprotein) value, the AUC value increased to 0.954 (ORsite138=12.26, p=0.017; ORAFP=3.64, p=0.022) which was markedly improved compared to AFP (AUC=0.867)(LR test p=0.0002) alone. However, in HBV- or HCV-related liver diseases, no significant site-specific change in core-fucosylation of ceruloplasmin was observed between HCC and cirrhosis.