Treatment of atherosclerosis or its prevention still represents one of the difficult challenges to modern medicine. Free radical peroxidation of LDL has been proposed to have a primary effect on the onset of diet-induced atherosclerosis. Melatonin has been shown to be potentially effective in prevention of some disorders in which free radical processes are involved. The purpose of this study was to investigate the possible protective effects of melatonin on high cholesterol fed animal arteries. Assessment of the atherosclerosis associated foam cells, intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was performed by histochemical and immuno-histochemical methods. Thirty adult male New Zealand rabbits were divided into three groups, ten animals each. Group-A served as control, group B&C were fed 1% cholesterol-rich diet for 6 weeks. Animals of group-C were drenched, at night, 510 ml saline solution containing 4.2 mg/kg/day melatonin. Frozen sections from the thoracic aorta were prepared for histochemical demonstration of peroxidase & acid phosphatase enzyme activities, and immuno histochemical display of ICAM-1 & VCAM-1. The enzyme activity and adhesion molecule expression were measured by computerized image analysis. Accumulation of peroxidase & acid phosphatase-rich foam cells was microscopically evident in the sub-endothelium of group-B arteries only. Enzyme activity and expression of ICAM-1 were significantly (p <0.0001) higher in group-B than group-C which was also higher than control, while VCAM-1 expression was significantly (p≤ 0.013) higher in group-B than control which was higher (p<0.00001) than group-C. In conclusion, the results indicate that melatonin could potentially be beneficial in prevention of the food induced atherosclerotic lesions.