Inhibitor of apoptosis (IAP) proteins represent promising therapeutic targets due to their high expression in many cancers. Here, we report that small-molecule IAP inhibitors at subtoxic concentrations cooperate with monoclonal antibodies against TRAIL receptor 1 (Mapatumumab) or TRAIL-R2 (Lexatumumab) to induce apoptosis in neuroblastoma cells in a highly synergistic manner (combination index <0.1). Importantly, we identify receptor-activating protein 1 (RIP1) as a critical mediator of this synergism. RIP1 is required for the formation of a RIP1/FADD/caspase-8 complex that drives caspase-8 activation, cleavage of Bid into tBid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Indeed, knockdown of RIP1 abolishes formation of the RIP1/FADD/caspase-8 complex, caspase activation and apoptosis upon combination treatment. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 inhibits IAP inhibitor- and TRAIL receptor-triggered apoptosis. In contrast, overexpression of the dominant-negative superrepressor IκBα-SR or addition of the tumor necrosis factor (TNF)α-blocking antibody Enbrel do not interfere with cotreatment-induced apoptosis, pointing to a nuclear factor-κB- and TNFα-independent mechanism. Of note, IAP inhibitor also sensitizes primary cultured neuroblastoma cells for TRAIL receptor-mediated loss of viability, underscoring the clinical relevance. By identifying RIP1 as a critical mediator of IAP inhibitor-mediated sensitization for Mapatumumab- or Lexatumumab-induced apoptosis, our findings provide new insights into the synergistic interaction of IAP inhibitors together with TRAIL receptor agonists.