Large-scale epidemiological studies have revealed a strong association between hypertriglyceridemia and coronary arteriosclerotic disease. However, there are conflicting reports whether the severe hypertriglyceridemia caused by lipoprotein lipase (LPL) deficiency is pro- or antiatherogenic. To determine the effect of LPL deficiency on atherosclerosis, we pursued long-term observation of the development of atherosclerotic lesions in an LPL gene deficient mouse model. At 4 months of age, homozygous LPL-deficient mice exhibited severe hypertriglyceridemia but no signs of aortic atherosclerotic lesions. At >15 months of age, these mice developed foam cell-rich atherosclerotic lesions at the aortic root, whereas wild-type and heterozygous mice were lesion-free at the same age. Further investigation revealed that plasma malondialdehyde levels in >15-month-old LPL-deficient mice were significantly higher than those of heterozygous and wild-type mice. Electron spin resonance analysis showed a marked increase in oxidative susceptibility of chylomicrons from the aged LPL-deficient mice. Incubation of chylomicrons from >15-month-old LPL-deficient mice with cultured human umbilical vein endothelial cells showed significantly increased upregulation of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, markers of enhanced endothelial activation, and enhanced adherence of human THP-1 mononuclear cells. These results clearly demonstrate the occurrence of spontaneous atherosclerosis in aged LPL-deficient mice mediated by the oxidation of chylomicrons and the activation of vascular endothelial cells.