Egypt has possibly the highest Hepatitis C Virus (HCV) prevalence worldwide. A high proportion of HCV infections become chronic and lead to liver cirrhosis and hepatocellular carcinoma (HCC). The cellular and molecular mechanisms behind HCV infection complication are not completely understood although apoptosis has been implicated in this process. Using flowcytometry, we examined whether T lymphocyte; isolated from patients with HCV and HCV-associated HCC (HCV-HCC); are predestined in vivo to undergo spontaneous apoptosis. Also, the role of p53; a key protein in apoptotic process; in the development of HCC was examined. Our data showed that T cells were severely depleted in HCV-HCC patients and its spontaneous apoptosis was higher in patient groups as compared to normal controls. In addition, p53 expression in liver tissue (determined by ELISA) was higher in the HCC patient groups as compared to normal controls and correlated well with the HCC grade. In conclusion, HCV infection induces peripheral T cell apoptosis, depletion and subsequently immune-suppression and this may lead to persistence of infection. Also, p53 is implicated in the poor prognosis of HCV-HCC and could be used as a predictive marker to assess the prognosis of HCC patients.