Through protein–protein binding assays, we found that HCV core protein interacted with 14-3-3ε protein. Interestingly, the expression of HCV core protein induced apoptosis in 293T cells. The apoptosis induced by core expression is accompanied by translocation of Bax from cytosol to mitochondria, disruption of mitochondrial membrane potential, cytochrome c release, and activation of caspase-9 and caspase-3. Furthermore, over-expression of 14-3-3ε inhibited the core-induced apoptosis and Bax translocation to mitochondria. These results indicate that HCV core protein induces the Bax-mediated apoptosis by interacting with 14-3-3ε protein in 293T cells. As a mechanism of apoptosis induction by HCV core, we propose that the interaction of HCV core with 14-3-3ε causes the dissociation of Bax from the Bax/14-3-3ε complex in cytosol, and the free Bax protein provokes activation of the mitochondrial apoptotic pathway.