To test the hypothesis that genetic susceptibility or resistance to diet-induced atherosclerosis is correlated with serum levels of specific lipids, lipoproteins, or apoproteins, male mice of a genetically susceptible and a genetically resistant strain were fed either a normal or an atherogenic diet. After 20 weeks on a normal diet, neither the resistant nor the susceptible strain mice had atherosclerosis; resistant strain mice had serum cholesterol of 66 +/- 11 while the susceptible strain mice had 90 +/- 1 mg/dl serum cholesterol, and lipoproteins were dominated by a single alpha-migrating HDL. After 20 weeks on an atherogenic diet, resistant strain mice had 185 +/- 55 mg/dl cholesterol, their lipoproteins remained dominated by alpha-migrating HDL, and two of eight mice had mild atherosclerotic lesions; susceptible strain mice had 510 +/- 94 mg/dl cholesterol, multiple alpha- and pre-beta-migrating lipoprotein species, and all 13 had advanced aortic atherosclerosis. The resistant strain mice had an apolipoprotein E/total lipoprotein protein ratio of 0.42 on the normal diet and 0.53 on the atherogenic diet, while the susceptible strain mice had the significantly lower ratios of 0.07 and 0.31, respectively. These data indicate that genetic resistance to diet-induced aortic atherosclerosis in mice is correlated with capacity to prevent large increases in serum cholesterol, to suppress abnormal alpha- and pre-beta-migrating lipoproteins, and to maintain elevated serum apolipoprotein E/total lipoprotein protein ratios. Our data do not preclude the possibility of additional gene control at the level of arterial end organ response.