Intestinal adaptation following small bowel resection (SBR) is associated with greater rates of enterocyte apoptosis by unknown mechanism(s). Since postresection adaptation is associated with increased translocation of luminal bacteria, we sought to characterize the role for the extrinsic, death receptor pathway for the activation of enterocyte apoptosis after massive SBR. We first performed SBR or sham operations in mice and the temporal expression of caspases 8, 9, and 3, death receptors TNFR₁ and Fas, and corresponding ligands (TNF and Fas-L) were determined in the remnant intestine at various postoperative time points. Ileal TNFR₁ and Fas expression were then measured after SBR in the setting of increased (waved-2 mice) or decreased (exogenous EGF administration) apoptosis. Finally, intestinal adaptation and apoptosis were recorded in the remnant ileum after SBR in TNFR₁-null and Fas-null mice. The expression of death receptor family proteins and caspases demonstrated only modest changes after SBR and did not correlate with the histologic appearance of apoptosis. In the setting of accelerated apoptosis, TNFR₁ and Fas expression were paradoxically decreased. Apoptotic and adaptive responses were preserved in both TNFR1-null and Fas-null mice. These results suggest that the mechanism for increased enterocyte apoptosis following massive SBR does not appear to involve the extrinsic, death receptor mediated pathway.