Background: Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, eTR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. Methods: a total of 18 3-d-old piglets were anesthetized and mechanically ventilated. six piglets received cecal ligation and perforation (cLP group) for induction of sepsis. six piglets also received continuous infusion (0.05 mg/kg/h) of eTR-P1/fl 30 min after cLP (eTR-P1/fl group). six piglets received a sham operation. serum total hydroperoxide (Th), biological antioxidant potentials (BaPs), oxidative stress index (OsI, calculated as Th/BaP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before cLP and at 1, 3, and 6 h after cLP. results: cLP evoked a state of shock resulting in elevated Th, OsI, and IL-6 levels. eTR-P1/fl administration after cLP resulted in lower serum Th at 1 and 3 h after cLP, OsI at 1 and 3 h after cLP, IL-6 at 1 and 3 h after cLP, and GOT at 3 and 6 h after cLP as compared with the cLP group. conclusion: eTR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (Th and OsI), IL-6, and GOT in a progressive neonatal sepsis cLP model.