Hepatocellular carcinoma (HCC) is triggered by many factors including infection with hepatitis C virus (HCV). However, the molecular basis of the development of HCV-related HCC remains unknown. The present study was designed to reveal the interference of the HCV infection in HCC patients with a set of anti-apoptotic factors, and expression levels of some molecular markers between HCV-related HCC and non-HCV-related HCC. We have determined the plasma circulating levels of Bcl-2, TGF-betaI, VEGF, beta2-MG and immunohistochemistry staining of p53 in HCV-related HCC patients (n = 40) and compared them in relation to both HCV-free HCC patients (n = 37) and normal control group (n = 20). The present data do not distinctly predict a significant role of HCV infection on the circulating Bcl-2 protein since in both HCC and HCC/HCV groups a limited number of patients have high levels of Bcl-2. However, TGF-betaI expression is markedly decreased in all patients, particularly in HCC associated with HCV. Moreover, serum VEGF is significantly higher in HCC patients with or without HCV infection than in normal control. No significant difference, however, was found between HCV-infected and HCV-free groups. Presence of HCV is associated with a high incidence of Loss of Heterozygosity (LOH) at M6P/IGFIIr site compared to HCV-free patients. Although beta2-MG is markedly elevated in all patients, a significant increase was observed in the presence of HCV. Immunohistochemical positive total staining for p53 protein was detected in 32/77 (41.5%); HCC-positive HCV was 21/40 (52.2%), and HCC-negative HCV was 11/37 (29.73%). Collectively, in HCC patients, HCV infection does not affect the levels of Bcl-2 and VEGF. beta2-MG and LOH levels at the M6P/IGFIIr site were higher in the presence of HCV concomitant with a decrease in TGF-beta1. There was no significant correlation between p53 and stage of the disease or between p53 protein expression and clinicopathological manifestations.