In this study, we assessed whether apolipoprotein E (APOE) polymorphism affects inflammatory responses and mortality in the caecal ligation and puncture model of peritonitis. In addition, we determined the effects of APOE mimetic peptide administration in this sepsis model. Differences in survival between targeted replacement mice expressing the human APOE3 allele (APOE3TR) and the APOE4 allele (APOE4TR) mice were assessed. In a separate series of experiments, COG1410, an apoE-mimetic peptide, was administered intravenously at 12-hour intervals for 72 hours and compared to vehicle-treated control animals. End-points included mortality and serum levels of interleukin-1beta, interleukin-6, interleukin-12 and tumour necrosis factor-alpha. Mice expressing the human APOE4 allele (n = 16) demonstrated an increase in mortality following caecal ligation and puncture compared with APOE3TR mice (n = 22; P = 0.039). Administration of the apolipoprotein E mimetic COG1410 was well tolerated and APOE3TR mice treated with peptide (n = 20) demonstrated a significant reduction in mortality compared with vehicle treated animals (n = 20; P = 0.007). A similar effect was also observed in APOE4TR animals, in which treatment with COG1410 was associated with reduced mortality compared with vehicle treatment (n =16 animals/group; P = 0.027). COG1410 was also associated with a reduction in TNFalpha, interleukin-1beta, interleukin-6 and interleukin-12 levels in both APOE3TR and APOE4TR (n = 5 animals/group) assessed at 24 hours. Thus, administration of an apolipoprotein E-mimetic peptide is well tolerated, suppresses inflammatory responses, and improves mortality in a caecal ligation and puncture model of sepsis.