Aim To test the hypothesis that Pioglitazone decrease CD40L expression in hypercholesterolemia rabbit aorta. Methods 15 male healthy New Zealand rabbits were randomly divided into three groups: control group(n=5)was fed with normal diet for eight weeks;high cholesterol group was fed with high-cholesterol diet for eight weeks;Pioglitazone treatment group(n=5)was fed with high-cholesterol diet for eight weeks supplemented with Pioglitazone [3 mg/(kg·d)] from the fourth week of cholesterol diet.CD40L was detected by immunohistochemistry, lectin-like oxidized low density lipoprotein receptor-1(LOX-1) mRNA was evaluated by reverse transcription-polymerase chain reaction(RT-PCR). Results Aortic intimal hyperplasia and smooth muscle cells proliferation in rabbits fed with high-cholesterol diet were decreased.Pioglitazone could improve high density lipoprotein and decrease the expression of CD40L and LOX-1 mRNA in hypercholesterolemia rabbits aorta. Conclusions Pioglitazone can inhibit the upregulation of LOX-1 in hypercholesterolemia rabbits aorta and decrease CD40L expression.These observation provide novel insight into a potential novel antiinflammatory and antiatherosclerosis pathway of thiazolidinediones.