Background: Hepatocellular carcinoma is a highly prevalent tumor globally and the world's second leading cause of cancer-related deaths. Glypican-3, a heparan sulfate proteoglycan expressed on the surface of HCC cells, has emerged as a new molecule with a strong link to occurrence and progression of HCC. Objective: This study was done to determine the role of Glypican-3 in diagnosis of HCC and its prognostic value following different treatment modalities. Patients and methods: The study included thirty patients with liver cirrhosis and HCC on top, and thirty patients with liver cirrhosis without HCC. Standard laboratory investigations, abdominal ultrasound and triphasic computed tomography were done for all patients. Serum alpha fetoprotein and Glypican-3 were measured in all patients before and one month after different treatment modalities. Results: Glypican-3 was significantly higher in HCC group (2.28 ± 0.97) in comparison to cirrhosis group (0.56 ± 0.31) with P-value <0.001. Glypican-3 level was higher in larger sized lesions with p value 0.023, one month after treatment with different modalities, Glypican-3 declined significantly (from 2.28 ± 0.97 to 1.44 ± 0.93) with p value <0.001. At a cutoff point of > 1.1 ng/ml Glypican-3 has 93.3% sensitivity, 96.67% specificity, 96.6% PPV and 93.5% NPV for detection of HCC. Conclusion: Glypican-3 can be a valuable diagnostic marker for HCC diagnosis and prognosis after various treatment modalities and may be complementary to alpha fetoprotein increasing overall sensitivity of HCC detection.