Previous characterization of mouse chromosome 2 identified genomic intervals that influence obesity, insulin resistance, and dyslipidemia. For this, resistant CAST/Ei (CAST) alleles were introgressed onto a susceptible C57BL/6J background to generate congenic strains with CAST alleles encompassing 67-162 Mb (multigenic obesity 6 [MOB6]) and 84-180 Mb (MOB5) from mouse chromosome 2. To examine the effects of each congenic locus on atherosclerosis and glucose disposal, we bred each strain onto a sensitizing LDL receptor-null (LDLR(-/-)) C57BL/6J background to predispose them to hypercholesterolemia and insulin resistance. LDLR(-/-) congenics and controls were characterized for measures of atherogenesis, insulin sensitivity, and obesity. We identified a genomic interval unique to the MOB6 congenic (72-84 Mb) that dramatically decreased atherosclerosis by approximately threefold and decreased insulin resistance. This region also reduced adiposity twofold. Conversely, the congenic region unique to MOB5 (162-180 Mb) increased insulin resistance but had little effect on atherosclerosis and adiposity. The MOB congenic intervals are concordant to human and rat quantitative trait loci influencing diabetes and atherosclerosis traits. Thus, our results define a strategy for studying the poorly understood interactions between diabetes and atherosclerosis and for identifying genes underlying the cardiovascular complications of insulin resistance.