Atherosclerotic plaques composed of foamed macrophages, smooth muscle cells and fibrous components in the twice-injured carotid artery from 1% cholesterol diet (HCD)-fed rabbits were prepared and the effects of all-cis-5, 8, 11, 14, 17-icosapentaenoic acid (EPA) on the histopathological properties of atherosclerotic lesions were examined. During the test period, there was no significant difference between the control and the EPA-treated groups in serum lipid levels. In the control group, atherosclerotic lesions were composed of foamed macrophages, smooth muscle cells and fibrous components. Some of the lesions had a large core of foamed macrophages covered with a thin cap of smooth muscle cells and fibrous components, and were morphologically similar to human vulnerable plaques. The classification of plaques, composing atherosclerotic lesions based on collagenous fiber density and foam cell size indicated that over 70% of plaques in the control group were poor in collagenous fiber, while about 20% of plaques contained only large foam cells. In contrast to the control group, over 70% of plaques in the EPA-treated group were rich in collagenous fiber and only 3% consisted of large foam cells. These results suggest that EPA changes certain aspects of pre-existing atherosclerotic lesions.