Serum glypican-3 versus alpha-fetoprotein as diagnostic markers for hepatitis C-associated hepatocellular carcinoma: a comparative study Background: Globally, hepatocellular carcinoma (HCC) is ranked as the fourth most frequent cause of death from cancer. The creation of more precise and sensitive blood markers, like Glypican-3 (GPC-3), for the early identification of HCC may improve patient survival. So, we aimed to compare the clinical significance of serum GPC-3 levels with AFP in the diagnosis of HCC on top of HCV-related liver cirrhosis. Methods: A case-control study was performed in the Hepatology and Gastroenterology Unit of the Internal Medicine Department at Zagazig University Hospitals. Ninety subjects were divided into Group I, which proved to be HCC patients. Group II: liver cirrhotic patients. Group III: Normal. All participants underwent a GPC-3 assessment. Results: Alpha-fetoprotein (AFP) was superior on serum Glypican-3 in diagnosis of liver cirrhosis, whereas the best cutoff was (≥19.5 Vs. ≥2.25), AUC (0.945 vs. 0.859), sensitivity (93.3% vs. 83.3%), specificity (76.7% vs. 70 %), PPV (80% vs. 73.5 %), NPV (92% vs. 80.8 %), and overall accuracy (85% vs. 76.7 %) respectively. In diagnosis of HCC, Glypican-3 was superior on AFP, whereas the best cutoff of AFP vs. serum Glypican-3 was (≥32.5 Vs. ≥3.65), AUC (0.858 vs. 0.873), sensitivity (80% vs. 90%), specificity (75% vs. 76.7 %), PPV (61.5% vs. 65.9 %), NPV (88.2% vs. 93.9 %), and overall accuracy (76.7% vs. 81.1 %) respectively. Conclusion: Serum GLP-3 could be a potential serum marker due to its high sensitivity and specificity in the detection of HCC.