This study aimed to detect the value of serum Glypican-3 (GPC3) in HCC Egyptian patients as a more specific, sensitive and accurate biomarker by comparing it with an established biomarker as AFP. Methods: This study was carried out on the following groups: group I: 50 healthy individuals served as control, group II: 100 HCV infection patients without any complications, group III: 100 HCV infected patients complicated with cirrhosis and group IV: 150HCVinfected patients complicatedwith (90 localized and 60 metastatic) HCC. Detection of serumGPC3 and alpha-fetoprotein using an enzyme-linked immunosorbent assay (ELISA) were done to all subjects. Results: When analysis of variance was done between the four groups, a highly statistical significant difference was found between these groups regarding the mean serum levels of AFP and GPC-3 where the highest increase of three markers were found in the HCC group. The combined AFP and Glypican-3 improve the sensitivity and specificity of AFP alone. Conclusions: GPC-3 could be a sensitive, specific and accurate marker for early detection of HCC diagnosis.