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In Egypt, hepatocellular carcinoma (HCC) is the second most common cancer in men and the sixth most common cancer in women. Approximately 10–20% of the Egyptian people are infected with hepatitis C virus (HCV). Glypican-3 (GPC-3), heat shock protein-70 (HSP-70), and clathrin heavy chain play critical roles in tumorigenesis.We carried out our study to test the alteration of the expression of GPC-3, HSP-70, and clathrin heavy chain during multistep hepatocarcinogenesis and to examine the relationship between the expression of these proteins and the clinicopathological features in HCC.We immunohistochemically examined the expression patterns of these proteins in 30 HCC specimens, 18 cirrhotic liver tissues near HCC, 30 chronic HCV specimens without HCC, and eight histologically normal liver tissues as a control group.There was significant upregulation of GPC-3, HSP-70, and clathrin heavy chain in hepatocellular carcinomas as compared with their expression in nonneoplastic liver tissue. A significant positive correlation was found between GPC-3 and tumor grade, size, and vascular invasion. Moreover, positive correlation was observed between HSP-70 and vascular invasion. Positive correlation was detected only between clathrin and histological grade of HCC.Our work provides the first indication about the expression pattern of GPC-3, HSP-70, and clathrin heavy chain in histologically unremarkable liver, chronic HCV-related cirrhosis, and HCCs among Egyptian patients. The upregulation of these proteins suggests their role in hepatocarcinogenesis. The diagnostic and therapeutic ramifications of our results await future investigations.