Background: Hepatocellular Carcinoma (HCC) is a complex disease; therefore it is firm to diagnose HCC with a single biomarker. Numerous diagnostic markers comprising of α-fetoprotein (AFP), glypican-3(GPC3) and squamous cell carcinoma antigen (SCCA) are associated with HCC. So, the search for a combination of biomarkers might provide valuable awareness for prognosis. Objectives: The aim of this study was to investigate the possibility of using serum GPC3 and SCCA as potential biological markers and their clinical significance as a strong indicator for the diagnosis of HCV related HCC. Subjects and methods: The study comprised two groups of patients (HCV related liver cirrhosis and HCC), each including 30 patients, additionally, 30 healthy individuals were included as a control group. Clinical and radiological features were documented. Liver function analyses and serum AFP were measured. Serum GPC3 and SCCA values were measured by ELISA technique. Results: A statistical significant increase (p