Background: Globally, hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related fatalities and is a highly prevalent tumor. A brand-new molecule with a significant connection to the pathogenesis and detection of hepatocellular carcinoma has emerged: glypican-3, a heparan sulfate proteoglycan expressed on the surface of hepatocellular carcinoma cells. Therefore, the purpose of this study is to determine whether Glypican-3 is used alone or in conjunction with α-fetoprotein (AFP) to diagnose hepatocellular carcinoma. Patients and Methods: This study was conducted on 75 patients with a history of chronic hepatitis C-related cirrhosis, Patients were divided into three equal groups. group I including cirrhotic patients without HCC, group II cirrhosis with HCC, and group III normal individuals serve as a control group. Serum levels of glypican-3 and α-fetoprotein (AFP) were measured, abdominal ultrasound, and triphasic computed tomography were done for all the study members. Serum alpha-fetoprotein measured by chemiluminescence and Glypican-3 was measured by enzyme linked immunosorbent assay (ELISA) kits. Results: The study included 40 male and 35 female arranged in the 3 groups. The age ranged between 43 and 65 with a mean of 41.98 in group 1, 55.4 in group 2, and 39.32 in group 3 which is statically significant. Glypican 3 (GLP3) with a cut-off>0.52 show a sensitivity of 96% and specificity of 94% while AFP with a cut-off>45 shows a sensitivity of 92% and specificity of 88%. GLP3 was more sensitive in the detection of the single focal lesion.