Mice derived from resistant A/J (A) and susceptible C57BL/6J (B) strains have been used to study the genetics of diet-induced atherosclerosis. A comparison of lesion scores between the parental strains, the F1 offspring of A x B and B x A matings and the offspring of (B x A)F1 hybrids backcrossed to either parent strain, indicates that a single major gene with alleles for resistance and susceptibility is responsible for the difference in response of A/J and C57BL/6J mice to a high fat, high cholesterol diet. By comparing the strain distribution pattern of susceptibility with known genetic markers in 30 A x B and B x A recombinant inbred (RI) strains, this gene, designated Ath-3, has been mapped close to a coat colour gene, c, on chromosome 7. Although a single gene may be primarily responsible for the difference in susceptibility to diet-induced atherosclerosis in these mice, the results of the breeding experiments indicate that its expression is probably modified by one or more additional genes.