Objective: Atherosclerosis is currently thought to be strongly associated with arterial stiffness. However, several clinical studies have shown no significant correlation between serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and arterial stiffness. This is in contradiction with that TC and LDL-C lead to atherosclerosis. Here, we explored and discussed the effect of blood lipid levels on arterial stiffness in ApoE-/- mice with or without atherosclerotic plaque formation. Design and method: ApoE-/- mice were fed with a normal chow diet (4.5 % fat, control group), a high-fat, high-cholesterol diet (40% fat, 1.25% cholesterol, HFHC group) and a high-fat diet (60 % fat, HF group) respectively. Body weight changes were recorded. Serum TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels were detected by automatic biochemical analyzer. PWV was measured by ultrasound, Russell-Movat’s pentachrome stain was used to detect structural arterial stiffening and oil red O stain was used to detect atherosclerotic plaque formation. Cell death was detected by flow cytometry and protein expression was measured by western blot. Results: After 14 weeks of feeding, a significant increase in PWV and a decrease in diastolic capacity and elastic fibers were observed in both HF and HFHC group. When the HFHC group atherosclerotic plaques appeared, no plaques were formed in the HF group. Serum TC, LDL-C, TG/HDL-C were significantly higher in the HFHC group than in the HF group, but TG, HDL-C, non-HDL-C, TC/HDL-C, non-HDL-C/HDL-C were not significantly different between the HFHC and HF group. In vitro, cholesterol crystals induced increase of death in mouse arterial endothelial cells, while knockdown of caspase-1 expression partially alleviated the cell death. Conclusions: Serum cholesterol, LDL-C, TG/HDL-C were higher in ApoE-/- mice with arterial stiffness increase and atherosclerotic plaques formation than in ApoE-/- mice with an equal increase in arterial stiffness but no plaque formation. Caspase-1-mediated pyroptosis of artery endothelial cell activated by cholesterol crystals may be an important mechanism leading to atherosclerotic plaque formation.