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.