To study the effect of CXCR4 antagonist AMD3100 on the atherosclerotic lesion, the expression of TNF-α and NF-κB and SDF-1α/CXCR4, so as to approach the specific role and possible mechanisms of SDF-1α/CXCR4 on atherosclerosis. 36 male apoE^-/- mice, 8 weeks old, randomly divided into three groups: ①normal food group, ② high fat group, ③AMD3100 group. Animals from high fat group and AMD3100 group were fed with western food which including 15% fat and 0.25% cholesterol. After feeding 12 weeks, all mice were anesthetized by 0.2～0.3 ml Urethane (20%) and removed eyeball in order to obtain blood preparation. Serum lever of SDF-1α was measured by ELISA. Serum triglyceride (TG), total cholesterol (TC), and high density lipoprotein cholesterol (HDL-C) were determined by commercially enzymatic methods. The Hematoxylin/Eosin dyeing of paraffin section was used to detect the area of atherosclerotic plaque of apoE^-/- mice aortic root transaction. The expression of CXCR4, TNF-α and NF-κB was analyzed by real time RT-PCR and Western blot, respectively. As a result, AMD3100 treatment resulted in a significant increase of atherosclerotic lesion area and the expression of TNF-α and NF-κB in apoE^-/- mice. Serum TG, TC, HDL-C and LDL-C concentrations were not markedly changed. AMD3100 reduced SDF-1α serum lever and CXCR4 expression on artery wall. It can be concluded that, atherosclerotic lesions in apoE-/- mice were aggravated by long term administration of CXCR4 antagonist AMD3100. Possible mechanisms of this action for AMD3100 are associated with the up-regulation pro-inflammatory factors TNF-α and NF-κB and down-regulation SDF-1α/CXCR4 axis.