Aim To construct the apolipoprotein CⅢ(ApoCⅢ) transgenic mice, and to hybridize with low density lipoprotein receptor(LDLR) knockout mice susceptible to atherosclerosis； To obtain the ApoCⅢ transgene＋LDLR defect(ApoCⅢ＋LDLR―/―) mice model； To study the effect of ApoCⅢ on atherosclerosis and its potential mechanism.Methods ApoCⅢ＋LDLR―/― mice and LDLR―/― mice were fed with high fat diet for 3 months. Plasma triglyceride, total cholesterol, lipid peroxidation products(8-isoprostane, malondialdehyde) and glutathione levels were detected. The whole aorta and aortic sinus of the mice were stained with oil red O and dihydroethidium(DHE). The RNA and protein in aorta were extracted and the expressions of related genes were analyzed. Results After feeding high fat diet, plasma triglyceride level in ApoCⅢ＋LDLR―/― mice was apparently higher than that in LDLR―/― mice, but there was no significant difference in total cholesterol levels. Whole aorta and aortic sinus dyeing showed a significant increase of atherosclerotic plaque. Plasma lipid peroxidation products(8-isoprostane, malondialdehyde) increased significantly and antioxidant glutathione reduced significantly in ApoCⅢ＋LDLR―/― mice. Aortic DHE staining showed that the level of reactive oxygen species increased significantly. The mRNA and protein expressions of the genes related to oxidative stress and endoplasmic reticulum stress were significantly increased in the aorta. The results prompted that ApoCⅢ could increase arterial oxidative stress and endoplasmic reticulum stress, thereby promoting the formation of atherosclerotic plaque. Conclusion ApoCⅢ has the role of promoting atherosclerosis, and its mechanism may be related to the increases of overall oxidative stress level and arterial wall oxidative stress, endoplasmic reticulum stress level.