To study the role of TDAG51 in atherosclerosis, male mice deficient in TDAG51 and apolipoprotein E (TDAG51−/−/ApoE−/−) were generated and showed reduced atherosclerotic lesion growth (56±5% reduction at 40 weeks, relative to ApoE−/− controls, P<0.005) and necrosis (41±4% versus 63±8% lesion area in TDAG51−/−/ApoE−/− and ApoE−/−, respectively; P<0.05) without changes in plasma levels of lipids, glucose, and inflammatory cytokines. Here, APOE is linked to atherosclerosis.