The association of copper with cardiovascular disease and a possible involvement of copper in the metabolism of cholesterol prompted the study on hypercholesterolemia mediated by copper deficiency. Copper deficient rats were found to exhibit a highly significant cholesterolemia (P less than 0.001), and plasma cholesterol showed a significant correlation with hepatic copper concentration (P less than 0.03). Two copper deficient rats died with hemothorax. The hearts of copper deficient rats were hypertrophied with large areas of hemorrhage, inflammation and focal necrosis. Prominent subendocardial fibroplasia was evident in copper deficient animals. The myocardial arteries of copper deficient rats were normal, however, aortas showed large areas of distorted and depleted elastic fibers. The results are discussed in terms of a possible role for copper in cholesterol metabolism, and in the pathogenesis of atherosclerosis.