To determine whether treatment with recombinant human tissue factor pathway inhibitor (TFPI), an inhibitor of the extrinsic coagulation pathway, can improve survival in a clinically relevant model of gram-negative sepsis, rabbits were given an intraperitoneal inoculation of a suspension containing hemoglobin (40 μg/mL), porcine mucin (150 μg/mL), and viable Escherichia coli O18:K1 (1.0 ± 0.5 × 105 cfu/kg). Treatment with gentamicin (5 mg/kg every 12 h for five doses) was instituted 4 h after induction of peritonitis. At the same time point, rabbits were randomized to receive a 24-h infusion of vehicle or one of three different doses of TFPI. Treatment groups, 7-day survival rates, and significance versus control were as follows: control, 1 of 20; TFPILOW DOSE (0.1 mg/kg, then 1 μg/kg/min), 3 of 12 (P = .14); TFPIMID DOSE, (0.5 mg/kg, then 5 μg/kg/min), 7 of 12 (P = .002); TFPIHIGH DOSE (10 mg/kg, then 10 μg/kg/min), 4 of 13 (P = .04). Thus, delayed treatment with TFPI improves survival in septic rabbits.