Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or A at position -463, and crossed these to the LDL receptor-deficient (LDLR(-/-)) mouse. The -463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high-fat-fed LDLR(-/-) mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR(-/-) males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and MPOA-expressing LDLR(-/-) males also exhibited significantly larger aortic lesions than control LDLR(-/-) males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.