Hepatocellular carcinoma (HCC) constitutes 70.48% of all liver tumors among Egyptians with multifactorial etiology and complex pathogenesis. HCV infection is the most common risk factor of HCC in Egypt, which commonly develops on top of cirrhosis (HCC-C); however, 15% to 20% of HCC are reported to arise in noncirrhotic livers (HCC-NC). This study aimed to explore the differences in the immunohistochemical expression of p53, c-Jun, c-Myc, and p21 between HCC-C and HCC-NC to verify the underlying molecular pathways and to study their role in hepatocarcinogenesis. This study investigated 103 cases of HCC (86 cases of HCC-C and 17 cases HCC-NC including tumorous and nontumorous tissues) together with 10 cases of chronic hepatitis and 10 cases of pure cirrhosis as control groups. Zero, 100%, 100%, and 50% of chronic hepatitis cases were positive for p53, c-Jun, c-Myc, and p21, respectively. All cirrhotic cases were negative for p53 and c-Jun, whereas they were all positive for c-Myc and p21. A total of 41%, 11.65%, 86.4%, and 57.3% of HCC cases showed p53, c-Jun, c-Myc, and p21 expression, respectively. The only difference between HCC-C and HCC-NC was the H-score values of p21 expression, which were higher in HCC-C compared with HCC-NC (P=0.03). HCV-related HCC commonly develops on top of cirrhosis with a minority develops on top of noncirrhotic liver. Only p21 pathway appears to be upregulated in favor of HCC-C than HCC-NC. p53 is considered as a late-event molecular carcinogen, whereas p21 and c-Myc may serve as early-event molecular carcinogen in HCC. The oncogenic role of p21 may be related to its cytoplasmic localization and its promotion of c-Myc expression. Progressive increase in the intensity of c-Myc expression from chronic hepatitis to cirrhosis to HCC may refer to its role as a multistep regulator of hepatocarcinogenesis. The marked reduction of c-Jun in HCC may refer to its tumor suppressor activity.