The MADD variant of the IG20 gene is necessary and sufficient for cancer cell survival. Abrogation of MADD, but not the other IG20 splice variants, can render cancer cells more susceptible to spontaneous as well as TRAIL (tumor necrosis factor alpha-related apoptosis-inducing ligand)-induced apoptosis. Both types of apoptosis in cells devoid of MADD can be inhibited by expression of CrmA or dominant-negative FADD, thereby suggesting that endogenous MADD may be targeting caspase-8 activation. Immunoprecipitation studies showed that MADD down-modulation could lead to caspase-8 activation at the death receptors without an apparent increase in the recruitment of death-inducing signaling complex components such as FADD. Further, we found that MADD can directly interact with death receptors, but not with either caspase-8 or FADD, and can inhibit caspase-8 activation. These results clearly demonstrate the importance of MADD in the control of cancer cell survival/death and in conferring significant resistance to TRAIL-induced apoptosis. In addition, our results indicate the therapeutic potential of MADD abrogation in enhancing TRAIL-induced selective apoptosis of cancer cells.