We previously reported that a human apolipoprotein E mimetic peptide, designated EpK, enhanced the ability of HDL in mediating cholesterol efflux and suppressing LPS-induced proinflammatory cytokine expression in culture macrophage. The aim of this study was to investigate the impact of this peptide on atherosclerosis in apolipoprotein E deficient (apoE^-/-) mice, employed lentivirus expression system to achieve the secretion of EpK in vivo. Eighteen female apoE^-/- mice at 11 months of age were randomly divided into two groups. All mice were injected with pWPI lentivirus (Lv-GFP control group) or pWPI/ EpK lentivirus (Lv-EpK) from retro-orbital venous plexus and fed with a chow diet. Blood samples were collected from mice to determine plasma lipids levels and paraoxonase-1 (PON1) activity during eighteen weeks after lentiviral injection. The extent of atherosclerosis was examined using Oil Red O-stained cross-sections of the aorta root and by en face analysis of the aorta. The mRNA levels of inflammatory cytokines in liver were measured by quantitative real-time PCR and the target protein levels in plasma were detected by Western blot. The results showed that EpK peptide was successfully detected in blood by secreting expression in the liver. There were no obvious differences in plasma lipids levels, lipoprotein profile, apolipoprotein AⅠ level and paraoxonase-1 (PON1) activity between two groups. However, the mean area of atherosclerotic lesions in Lv-EpK mice was significant reduced in aortic arch and total aorta, compared with Lv-GFP control groups (the lesion area of aortic root was (0.87±0.07) mm² vs (1.03±0.08) mm², P < 0.05; the percent area of aortic lesion area was 42% vs 55.8%, P < 0.01). Moreover, expression of EpK resulted in significantly reduced plasma serum amyloid A (SAA) levels and the mRNA levels of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) in mouse liver. These results suggest that the apoE mimetic peptide EpK, is able to reduce atherosclerotic plaque in apoE^-/- mice, which the mechanism may be involved in its anti-inflammatory property.