The effects of apolipoprotein (Apo) AI mimetic peptide synthesized from D- and L-amino acids on atherosclerotic lesion formation were investigated in low-density lipoprotein (LDL) receptor-deficient mice on a Western diet and in apoE null mice. In addition, their effects on the inflammatory changes induced in LDL-receptor mice fed a Western diet following influenza A infection were studied. When apolipoprotein AI mimetic peptides synthesized from either D- or L-amino acids were administered to LDL-receptor null mice, only peptides synthesized from D-amino acids were stable in the circulation and enhanced the ability of high-density lipoprotein (HDL) to protect LDL against oxidation. Administration of the peptide D-4F to LDL-receptor null mice and apoE null mice decreased lesion size. Additionally, in LDL receptor null mice after influenza infection, D-4F treatment increased plasma HDL levels and paraoxonase activity, and inhibited increased in LDL-cholesterol and peak levels of interleukin-6 post-infection. Injection of female mice with male macrophages, and subsequent measurement of the male 'sry' gene, revealed a marked increase in macrophage traffic into the aortic arch after infection that was prevented by administration of D-4F. This indicates that: (i) oral D-4F has powerful anti-atherosclerotic properties, and (ii) the loss of the anti-inflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.