We previously identified a G>A single nucleotide polymorphism (SNP) between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains at position 2077 in the coding region of Vcam1 that leads to substitution of an amino acid from aspartic acid (D) to asparagine (N) in the protein product. In the present study, we investigated the association of this SNP with atherosclerosis susceptibility using a panel of inbred mouse strains, a set of recombinant inbred (RI) strains derived from B6 and C3H mice, and a cohort of F2 mice derived from B6 and C3H apolipoprotein E-deficient (apoE(-/-)) mice. Inbred strain analysis revealed that mouse strains with the B6 Vcam1 genotype developed significantly larger atherosclerotic lesions than strains with the C3H genotype (4622+/-2816 microm(2)/section versus 362+/-697 microm(2)/section; P=0.029). BXH RI strains with the B6 Vcam1 genotype also developed larger atherosclerotic lesions than those with the C3H genotype (8305+/-9031 microm(2)/section versus 2139+/-2931 microm(2)/section) although the difference was not statistically significant (P=0.13). In contrast, no association was detected between Vcam1 and atherosclerotic lesion size in F2 mice. The present data indicate that the G>A mutation of Vcam1 is associated with atherosclerotic lesion formation in the dietary but not apoE(-/-) models of atherosclerosis and this association suggests a role for the Vcam1 gene in influencing atherosclerosis susceptibility.