Enteropathogenic E. coli (EPEC) is an attaching an effacing (A/E) pathogen that adheres intimately to the apical surface of host enterocytes and causes acute gastroenteritis in humans. Like other enteric bacterial pathogens such as Salmonella and Shigella, EPEC utilises a type III secretion system (T3SS) to deliver multiple effector proteins directly into host cells where they subvert various cellular processes including apoptosis and inflammatory signaling. In this study, we found that the T3SS effector, NleB interrupted host extrinsic apoptotic signaling via the death receptors, TNFR1 and FAS. NleB expressed ectopically or delivered by the T3SS bound to the death domain (DD) proteins FADD, RIPK1 and TRADD in a DD dependent manner thereby preventing FasL and TNF-induced caspase-8 activation and cell death. Furthermore, NleB inhibited the formation of the death inducing signaling complex (DISC) during EPEC infection. This activity was dependent on the N-GlcNAc transferase activity of NleB1, which specifically modified Arg117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing (A/E) pathogens antagonise extrinsic cell death pathways to prevent apoptosis of infected cells, thereby interfering with a major antimicrobial host response.