Persistent hepatitis C virus (HCV) infection is associated with the development of human hepatocellular carcinoma (HCC), although the mechanism of HCV-related hepatocarcinogenesis remains unclear. bcl-2 oncoprotein can prolong cell survival by blocking apoptosis without affecting cellular proliferation. Transforming growth factor alpha (TGF-) is alleged to play a role in malignant progression as well as normal cell growth in an autocrine manner. The present study was carried out to investigate the kinetics of bcl-2, Transforming growth factor alpha (TGF-) and alpha-fetoprotein (AFP) release in sera, ascitic fluid and liver tissue of chronic hepatitis virus C (HCV) infected patients and those with hepatocellular carcinoma (HCC). The impact of these biomarkers on the development of HCC was also investigated. Serum bcl-2 levels were significantly higher (P<0.001) in HCV and HCC compared to the healthy control group and in HCC patients compared to HCV patients. This may suggest that the antiapoptotic oncoprotein bcl-2 may provide hepatocytes with sufficient time in the inflamed tissue to accumulate the specific gene mutations that culminate cancer. This work showed that serum TGF-level was significantly higher in HCV and HCC patients (P<0.001) as compared to the healthy control adults. However, there was non-significant difference in serum TGF-level in HCV patients as compared to those with HCC. This finding could suggest that TGF-might be the primary marker to start the process of carcinogenesis, however, higher levels of TGF- may not be needed to the progress of malignancy. Serum TGF-levels were significantly higher (P<0.05) in HCV patients with liver cirrhosis than HCV patients without cirrhosis. This might suggest that the hepatocyte regeneration occurring in cirrhosis could contribute to the higher serum TGF-levels in HCV patients with liver cirrhosis. The sensitivity and specificity to detect HCC in HCV patients were 62.5% and 90.9% for serum bcl-2; 37.5% and 68.2% for serum TGF-; 56.3% and 90.1% for AFP. In conclusion, bcl-2 oncoprotein over-expression in hepatocytes in HCV suggests that the available mechanism of apoptosis may be suppressed by bcl-2. The increased expression of bcl-2 oncoprotein in HCC, by its antiapoptotic action, is essential for carcinogenesis to proceed to malignancy. Serum bcl-2 may be helpful for diagnosis of HCC developing in HCV patients. Although the increased expression of bcl-2 oncoprotein in HCC suggests that bcl-2 may be involved in hepatocarcinogenesis, further investigations through molecular techniques is necessary, in order to define the exact role of apoptosis-related genes in this neoplastic process.