Most of the investigations for an alternative medicinal treatment on atherosclerosis have been focused on natural or dietary compounds including phytochemicals. So far, few studies regarding anti-atherosclerotic small peptides except for tetrapeptide of Lys-Arg-Glu-Ser have been reported. The present study was, thus, to investigate whether dipeptide Trp-His, which is one of vasodilating small peptides, could reduce atherosclerotic lesions in apo E-deficient mice fed a high-fat diet. The animal study involved a 9-week-successive administration of Trp-His at a dose of 0, 10 or 100 mg/kg per d. After 9-week administration, en face analyses provided the first direct evidence that the atherosclerotic lesion area was significantly reduced by 27 and 38 % for Trp-His dosed at 10 and 100 mg/kg per d, respectively, compared with the control group. Administration of Trp-His did not affect growth parameters such as body weight and feeding efficiency (P>0.1). Total serum cholesterol and HDL-cholesterol as well as lipid profiles in the liver did not differ between the tested groups. Taken together, the anti-atherosclerotic effect of dipeptide Trp-His should be addressed into physiological functions of bioactive peptides, in which the dipeptide may elicit the power by alternative mechanism(s), not by the regulation of lipid metabolism.