A therosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This “oxidation hypothesis” has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E–deficient mice (apo E^–/–/L-12LO^–/–). In chow-fed 15-week-old apo E^–/–/L-12LO^–/– mice, the extent of lesions in whole-aorta en face preparations (198 ± 60 μm²) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase–expressing controls (apo E^–/–/L-12LO^+/+), which showed areas of lipid deposition (15,700 ± 2,688 μm²) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E–deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E^–/–/L-12LO^–/– mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.