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Group V secretory phospholipase A2 (GV sPLA2) has been detected in both human and mouse atherosclerotic lesions. This enzyme has potent hydrolytic activity towards phosphatidylcholine-containing substrates, including lipoprotein particles. Numerous studies in vitro indicate that hydrolysis of high density lipoproteins (HDL) and low density lipoproteins (LDL) by GV sPLA2 leads to the formation of atherogenic particles and potentially proinflammatory lipid mediators. However, there is no direct evidence that this enzyme promotes atherogenic processes in vivo.We performed gain-of-function and loss-of-function studies to investigate the role of GV sPLA2 in atherogenesis in LDL receptor–deficient mice. Compared with control mice, animals overexpressing GV sPLA2 by retrovirus-mediated gene transfer had a 2.7 fold increase in lesion area in the ascending region of the aortic root. Increased atherosclerosis was associated with an increase in lesional collagen deposition in the same region. Mice deficient in bone marrow–derived GV sPLA2 had a 36% reduction in atherosclerosis in the aortic arch/thoracic aorta.Our data in mouse models provide the first in vivo evidence that GV sPLA2 contributes to atherosclerotic processes, and draw attention to this enzyme as an attractive target for the treatment of atherosclerotic disease.