Lipoprotein phospholipid plays a major role in neutralization of endotoxin. This study tested the hypothesis that prophylactic administration of a phospholipid (PL)enriched emulsion (PRE), which augments phospholipid content of serum lipoproteins and neutralizes endotoxin in-vitro, would preserve cardiovascular function and improve survival in porcine septic peritonitis. A control group was compared to low, mid and high dose treatment groups that received PRE by primed continuous infusion for 48 hours. A fibrin clot containing live E. coli O111.B4 was implanted intraperitoneally 30min after the priming dose. Survival increased in a dose dependent manner and was correlated with serum PL. Infused PL was associated with HDL in the low-dose group and all serum lipoproteins at higher doses. Treatment significantly lowered serum endotoxin and TNF-, preserved cardiac output and ejection fraction, and attenuated increases in systemic and pulmonary vascular resistances. This study demonstrated for the first time that augmentation of lipoprotein phospholipid via administration of protein free phospholipid emulsion improved survival and offers a novel therapeutic approach to sepsis.