Background: Although surgery is the treatment of choice of hepatocellular carcinoma, only 5-10% of their patients are candidates for surgical resection. Numerous proteins and receptors are over expressed on hepatocellular carcinoma (HCC) cell membrane including glypican3 (GPC3). It has attracted substantial attention because its expression is correlated with HCC tumorigenesis and prognosis. Objective: To assess the diagnostic role of Glypican-3 levels in diagnosis of hepato-cellular carcinoma. Patients and methods: This was a prospective comparative study conducted on 90 cases from the outpatient Clinic of Internal Medicine Department of Sayed Galal Hospital and Ahmed Maher Teaching Hospital. The patients of the study were classified into three equal groups: Group 1: Patients with liver cirrhosis and HCC on top (diagnosed by abdominal ultrasonography and abdominal CT with oral and IV contrast), Group 2: Patients with liver cirrhosis and no evidence of HCC, and Group 3: Patients of healthy people as a control group for comparison. Results: Non-significant differences between groups regarding age, gender, Hb concentration, platelets (PT) INR, AST, ALT, viral markers in cirrhotics and HCC patients. GPC-3 showed higher level in cirrhotics and HCC patients with a significant over-expression in HCC. Patients with over expression of GPC-3 have significant elevation of PT, serum bilirubin. The presence of mass nodule was significantly present in HCC group, while multiple nodularity commonly present in cirrhotics but this did not deny its presence of HCC. Conclusion: GPC-3 level is important in diagnosis and its differentiation from benign conditions.