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Atherosclerosis is the underlying cause of heart attack, ischemic stroke and peripheral arterial disease, and genetic factors involved remain mostly unidentified. We previously identified a significant locus on mouse chromosome 17 for atherosclerosis, Ath49, in an intercross between BALB/c and SM strains. Ath49partially overlaps in the confidence interval with Ath22mapped in an AKR × DBA/2 intercross. Bioinformatics analysis prioritized Mep1a, encoding meprin 1α metalloendopeptidase, as a likely candidate gene for Ath49. To prove causality, Mep1a−/−Apoe−/−mice were generated and compared with Mep1a+/+Apoe−/−mice for atherosclerosis development. Mep1awas found abundantly expressed in atherosclerotic lesions but not in healthy aorta and liver of mice. Mep1a−/−Apoe−/−mice exhibited significant reductions in both early and advanced lesion sizes. Loss of Mep1aled to decreased necrosis but increased macrophage and neutrophil contents in advanced lesions, reduced plasma levels of CXCL5 and an oxidative stress biomarker. In addition, Mep1a−/−mice had significantly reduced triglyceride levels on a chow diet. Thus, Mep1ais a susceptibility gene for atherosclerosis and aggravates atherosclerosis partially through action on oxidative stress and inflammation.