<p>Procaspase-8 activation at the death-inducing signalling complex (DISC) is largely blocked by short c-FLIP isoforms (c-FLIP_S). The interaction between c-FLIP_S and procaspase-8 is mediated by their tandem death effector domains (tDED). The canonical model of tDED interaction suggests that c-FLIP_S uses H1a/H4a α helices of DED1 to interact with the H2b/H5b α helices of procaspase-8 DED2. Here, based on the NMR chemical shift perturbation of c-FLIP_S (F114G) resonances induced by titration with peptides derived from the helical regions of procaspase-8, a model structure of the c-FLIP_S:procaspase-8 complex was constructed using HADDOK. The complex revealed that their interactions are mediated by the two binding clefts on DED1 of c-FLIP_S and helices H1a/H4a of procaspase-8, the two clefts are formed by the α helices H1a, H5a, and H7a. The binding clefts on DED1 of c-FLIP_S were also suggested to bind nuclear factor kappa B (NF-κB) essential modulator (NEMO) and initiate NF-κB pathway activation. To further investigate the interaction between c-FLIP_S and NEMO, a c-FLIP_S:NEMO complex model was also constructed. Two complex structural models revealed that c-FLIP_S may interact with procaspase-8 and NEMO via a common binding surface. Furthermore, we hypothesized that c-FLIP_S uses a similar binding surface to interact with both procaspase-8 and NEMO, thereby promoting cell survival by inhibiting caspase-8 activation and inducing NF-κB activity.</p>