Aim To study the effect of the combined peroxisome proliferator activated receptor （PPAR） ligand （pioglitazone） and MEK1/2 inhibitor （U0126） on the development of atherosclerosis in ApoE deficient （ApoE^－/－） mice and define the underlying mechanisms. Methods Male ApoE^－/－ mice （8 Week-old） were randomly divided into three groups and received the following treatment:high fat diet （HFD）,HFD containing pioglitazone,HFD containing pioglitazone plus U0126. The treatment was lasted for 16 weeks with routine check of food intake,water drinking and bodyweight gain. At the end of treatment,all the mice were anesthetized and euthanized in a CO₂ chamber followed by collection of blood,aorta and liver. The serum was prepared followed by determination of triglycerides （TG）,total cholesterol,HDL-cholesterol and LDL-cholesterol levels using commercially available enzymatic kits. The 5 μm frozen sections of aortic root were prepared,and lesions in enface aorta and the aortic root cross sections were determined by oil red O staining. The liver frozen sections were prepared and used to determine hepatic lipid content by oil red O staining. A piece of liver （～50 mg） was used to extract total lipids followed by TG quantitative analysis. Results The treatment had little effect on serum lipid profiles as well as hepatic TG levels. However,pioglitazone significantly inhibited the development of atherosclerosis and the inhibition was enhanced by adding U0126. The combined pioglitazone and U0126 increased lesion stability by increasing collagen and elastin content in aortic wall. Conclusions The combined pioglitazone and U0126 inhibits the development of atherosclerosis without side effects,such as fatty liver disease and liver damage. Our results provide a new approach for treatment of atherosclerosis.