To study the possibility that susceptibility to the development of atherosclerosis during chronic renal failure is genetically determined, aortic lesion formation and changes in serum lipid levels in mice of 2 different inbred strains, C57BL/6J and A/J, were examined. Chronic uremia was induced by electrocoagulation of the right renal cortex and left nephrectomy. The mice were then fed either normal rodent chow or a saturated fat and cholesterol-enriched diet for 6 weeks. None of the A/J mice developed atherosclerosis, whereas the aortas of chow-fed uremic C57BL/6J mice were found to contain a number of fatty lesions, the severity of which was increased by a high fat diet. Uremia had different effects on serum cholesterol, triglycerides, and lipoproteins in the two strains. The results suggest that the resistance of A/J mice to uremia-induced atherosclerosis may be attributed to their ability to maintain high serum HDL-cholesterol levels and/or low serum triglyceride levels. The results further indicate that the development of atherosclerotic lesions in uremic mice is both genetically determined and affected by diet.