Abstract Background: Early diagnosis and treatment of HCC can greatly improve the efficiency of treatment and extend patient life. Aim of Study: To investigate the expression of serum Glypican-3 (GPC3) in patients with Hepatocellular Carcinoma (HCC) and determine its efficacy as a screening test in early detection of HCC. Patients and Methods: This case control study involved 30 HCC patients, 30 liver cirrhotic patients and 20 healthy controls. This study had been approved by local institutional research board in Menoufia Faculty of Medicine. All subjects participated in the study voluntarily and written informed consent was obtained from each participant. Clinical exami-nation, abdominal ultrasonography and triphasic Computed Tomography (CT) for focal lesion were performed. Liver function tests were performed using clinical auto-analyzer, serum a-Fetoprotein (AFP) was measured using Enzyme-linked Immune-Sorbent Assay (ELISA) method and GPC3 was determined by ELISA kit for GPC3. Data were collected and statistically analyzed. Results: GPC3 was highly significant higher in HCC group than cirrhotic and control groups. There was highly positive significant correlation between GPC3 and child score, size of focal lesions and number of focal lesions. The sensitivity of GPC3 in diagnosis of HCC was (68.5%) and the specificity was (83.3%) at cut off point (58.2ng/ml) that elicited from the Receiver Operator Characteristic (ROC) curve with very good Area Under Curve (AUC) (0.814), whereas that the sensitivity of AFP was (66.7%) and the specificity was (66.7%) at cut off point (380ng/ml) that elicited from the ROC curve with very good AUC (0.679). Conclusion: GPC3 is highly associated with HCC and is more sensitive than AFP for early detection of HCC.