Recent evidence suggests that apoptotic cell death plays an important role in the pathophysiology of sepsis. Because there is extensive apoptosis of vascular endothelial cells in sepsis, we examined whether the death receptor pathway of apoptotic signaling is altered in thoracic aortas from mice with polymicrobial sepsis, as produced by cecal ligation and puncture (CLP). In septic aorta, total and surface expression levels of the two death receptors, tumor necrosis factor receptor 1 and Fas, were highly up-regulated. Furthermore, marked increases in the mRNA and protein levels of Fas-associated death domain (FADD), an adaptor molecule to recruit procaspase-8 into the death-inducing signal complex, were observed in septic aorta, which were strongly suppressed by systemic delivery of small interfering RNA (siRNA) against FADD. No increase in expression of death receptors and FADD was observed in endothelium-denuded aortic tissues from septic animals. Systemic administration of FADD siRNA also resulted in great attenuation of sepsis-induced increases in expression and activation of caspase-3, an effector protease in the apoptosis cascade. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) revealed that the significant appearance of cell apoptosis in aortic endothelium after CLP-induced sepsis was eliminated when FADD siRNA was systemically applied. Light and electron microscopic examinations of septic aorta showed cell swelling, nuclear fragmentation, and partial detachment of endothelial cells from the basal membrane, which were prevented by systemic treatment with FADD siRNA. Finally, FADD siRNA administration dramatically improved survival of CLP mice, supporting the feasibility of this gene-based approach for treating septic shock.