Systemic inflammation induces a multiple organ dysfunction syndrome (MODS) that contributes to morbidity and mortality in septic patients. Since increasing plasma apolipoprotein (apo) A-I and HDL may reduce the complications of sepsis, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in rats undergoing cecal ligation and puncture (CLP) injury. Male Sprague-Dawley rats were randomized to undergo CLP or sham surgery. Interleukin-6 (IL-6) levels were significantly elevated in plasma by 6 hrs after CLP surgery compared to shams. In subsequent studies, CLP rats were further subdivided to receive vehicle or 4F (10 mg/kg) by intraperitoneal injection, 6 hours after sepsis induction. Sham-operated rats received saline. Echocardiographic studies showed a reduction in left ventricular (LV) end-diastolic volume, stroke volume and cardiac output (CO) 24 hrs after CLP surgery. These changes were associated with reduced blood volume and LV filling pressure. 4F treatment improved blood volume status, increased CO and reduced plasma IL-6 in CLP rats. Total cholesterol (TC) and HDL were 79±5 and 61±4 mg/dL, respectively, in sham rats. TC was significantly reduced in CLP rats (54±3), due to a reduction in HDL (26±3). 4F administration to CLP rats attenuated the reduction in TC (69±4) and HDL (41±3) and prevented sepsis-induced changes in HDL protein composition. Increased plasma HDL in 4F-treated CLP rats was associated with an improvement in CO and reduced mortality. It is proposed that protective effects of 4F are related to its ability to prevent the sepsis-induced reduction in plasma HDL.