Hepatitis C virus (HCV) often causes chronic infection in humans, although the mechanisms for viral chronicity are not clearly understood. Tumor necrosis factor-α (TNF-α)-mediated apoptosis is a key element in a host organism's defense inhibiting viral spread and persistence. HCV has evolved mechanisms that antagonize host cell death signals so that virus propagation can continue unabated in infected cells. HCV core protein blocks TNF-α-mediated apoptosis signaling and inhibits caspase-8 activation by sustaining the expression of cellular FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP). HCV core protein also blocks TNF-induced proteolytic cleavage of the death substrate poly (SDP-ribose) polymerase from its native 116-kDa protein to the characteristic 85-kDa polypeptide. A decrease in endogenous c-FLIP by specific small-interfering RNA induces TNF-α-mediated apoptotic cell death and caspase-8 activation. However, HCV core neither affects the association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD) nor TRADD-Fas-associated death domain protein (FADD) and procaspase-8. Thus, HCV core protein appears to play a role in the inhibition of TNF-α-mediated cell death. This chapter describes methods to identify inhibitory mechanism of HCV for TNF-α-mediated apoptosis.