To determine whether recombinant inbred strains derived from C57BL/6J and A/J mice would provide a good model in which to study the genetics of diet-induced atherosclerosis, male mice of the parent strains were compared in a number of experiments designed to correlate various biochemical changes with susceptibility or resistance to the disease. In both strains fed an atherogenic diet containing 27% coconut oil and 4.5% cholesterol, there was a significant rise in serum very low-density plus low-density lipoprotein cholesterol levels, but only C57BL/6J mice developed discernible fatty lesions in the aortic wall. In A/J mice a significant rise in high-density lipoprotein cholesterol was also observed, which corresponded to the appearance of a second species of high-density lipoprotein in the serum, but in C57BL/6J mice there was a fall. In susceptible C57BL/6J mice, free cholesterol is secreted into bile, which becomes supersaturated, leading to the formation of gallstones. In the resistant strain, however, dietary cholesterol accumulates in the liver. A difference in hepatic cholesterol metabolism between the two strains may thus be a factor in determining their different susceptibilities to diet-induced atherosclerosis.