Human cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector C (CIDEC) is a potent apoptotic inducer. Previous studies have indicated that the Fat-specific protein 27 (Fsp27), a mouse homolog of CIDEC, induces apoptosis via caspase-3, -7, and -9 and triggers the release of cytochrome c from mitochondria, which implies that the mitochondrial pathway is involved in Fsp27-induced apoptosis. In the current study, we found that CIDEC-induced apoptosis was mediated by caspase-8. The caspase inhibitor assay showed that CIDEC-induced apoptosis was dramatically reduced in the presence of the general caspase inhibitor, the caspase-3 inhibitor, and the caspase-8 inhibitor, whereas the caspase-9 inhibitor only weakly inhibited CIDEC-induced apoptosis. These results confirmed that the activation of caspase-3 and caspase-8 were involved in CIDEC-induced apoptosis. Moreover, in caspase-3- or caspase-8-deficient cells, CIDEC-induced apoptosis were dramatically decreased, which demonstrated that CIDEC-induced apoptosis might require the activation of caspase-3 and caspase-8. Because caspase-8 in general is a key effecter of death-receptor pathway and activated by Fas-Associated protein with Death Domain (FADD), we examined whether FADD was involved in CIDEC-induced apoptosis. Our results demonstrated that CIDEC-induced apoptosis was independent of FADD, suggesting that CIDEC-induced apoptosis might be in a death-receptor-independent, caspase-8-dependent manner. It was also found that the region of amino acid 168-200 in carboxyl domain of CIDEC was critical for its crucial pro-apoptotic function.