The hepatitis C virus (HCV) core protein is a multifunctional protein. It may bind to the death domain of tumor necrosis factor receptor 1 (TNFR1) and to the cytoplasmic tail of lymphotoxin-β receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. In vitro studies have been inconclusive regarding its ability to inhibit or enhance TNF-α–induced apoptosis. To address this issue, electrophoretic mobility shift assay (EMSA) and immunohistochemical studies were used to show the activation of nuclear factor κB (NF-κB) in HCV-infected liver tissues and in HCV core–transfected cells. The activation of NF-κB was correlated with the apoptosis assays. The results showed that NF-κB activation could be shown in HCV-infected livers and HCV core–transfected cells. The data of EMSA correlated with those of immunohistochemical studies, which revealed a higher frequency of NF-κB nuclear staining in HCV-infected than in normal livers. NF-κB activation conferred resistance to TNF-α–induced apoptosis in HCV core–transfected cells. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate sensitized them to TNF-α–induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-κB and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.