The diarrheagenic pathogen enteropathogenic Escherichia coli (EPEC) limits the death of infected enterocytes early in infection. A number of bacterial molecules and host signaling pathways contribute to the enhanced survival of EPEC-infected host cells. EspZ, a type III secreted effector protein that is unique to EPEC and related "attaching and effacing" (A/E) pathogens, plays a role in limiting host cell death, but the precise host signaling pathways responsible for this phenotype are not known. We hypothesized that EspZ contributes to the survival of infected intestinal epithelial cells by interfering with apoptosis. Consistent with previous studies, scanning electron microscopy analysis of intestinal epithelial cells infected with an EPEC espZ mutant (ΔespZ) showed increased levels of apoptotic and necrotic cells compared to cells infected with the isogenic parent strain. Correspondingly, higher levels of cytosolic cytochrome c and increased activation of caspases 9, 7, and 3 were observed for ΔespZ strain-infected cells compared to wild-type (WT) EPEC-infected cells. Finally, espZ-transfected epithelial cells were significantly protected from staurosporine-induced, but not tumor necrosis factor alpha (TNF-α)/cycloheximide-induced, apoptosis. Thus, EspZ contributes to epithelial cell survival by mechanisms that include the inhibition of the intrinsic apoptotic pathway. The enhanced survival of infected enterocytes by molecules such as EspZ likely plays a key role in optimal colonization by A/E pathogens.