This report describes the features of developing atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of human familial hypercholesterolemia. Observations were made in 18 homozygous WHHL rabbits, aged 4 days to 15 months, fed standard rabbit chow; seven control New Zealand white rabbits fed a similar diet, and four New Zealand white rabbits fed rabbit chow containing 2% cholesterol and 10% corn oil for 2 weeks. The WHHL rabbits showed evidence of progressive disease of the aorta with accumulation of strongly birefringent lipid in intimal lesions, including fatty streaks, raised foam cell lesions, and plaques (atheromas), as well as in the media. As seen by electron microscopy, the cellular population of the intimal lesions consisted predominantly of smooth muscle cells with lipid deposits and lipid-laden foam cells. Lipid deposits occurred as cytoplasmic neutral lipid droplets and as multilamellar bodies. In addition to advanced atherosclerosis of the aorta, a 15-month-old WHHL rabbit also had focal coronary atherosclerosis and subcutaneous xanthomas. The New Zealand white rabbits fed a high cholesterol and fat diet for 2 weeks showed early intimal lipid accumulation in the aorta and prominent lipid accumulation in hepatocytes and macrophages of the liver and spleen. New Zealand white rabbits fed the standard rabbit chow had no abnormal lipid deposits. In contrast to the cholesterol-fed rabbits, WHHL rabbits had only mild lipid accumulation in other tissues. Thus, many similarities exist between atherosclerotic disease in the WHHL rabbit and in man. This study shows that the WHHL rabbit is a good model of familial hypercholesterolemia.