Objective To investigate the effect of 7-difluoromethoxy-5,4′-dimethoxygenistein (DFMG) on the angiogenesis and plaque stability in the atherosclerosis model of the Apolipoprotein E knockout mice (ApoE-/-). Methods A total of 20 ApoE-/- mice were randomly divided into 4 groups (n=5): model group, solvent (DMSO) group, DFMG group, and lovastatin group. And 5 C57BL/6 mice were assigned to the blank control group. The blank control group was fed with normal diet and other 4 groups were fed with highfat diet to induce atherosclerosis model. DFMG of 10 mg/(kg·d) was given to the mice of the DFMG group, and lovastatin 5 mg/(kg·d) to those of the lovastatin group. After 16 weeks, lipid content in the mice serum was measured by automatic biochemical analyzer. The lipid deposition in the gross thoracic aorta was evaluated by oil red O staining. The plaque stability in the thoracic aorta was measured by Masson staining. The angiogenesis was measured by the immunohistochemical staining with VEGF and vWF antibodies. The protein levels of TLR4 in the thoracic aorta were detected by Western blotting. Results DFMG decreased the ratio of atherosclerotic plaque to intraluminal diameter (P<0.05), reduced the levels of plasma lipids, including LDL, VLDL, TG and CHOL (P<0.05), and attenuated the amount of lipid red stains in the thoracic aorta (P<0.05), increased collagen in the plaque (P<0.05) and lowered the expression of VEGF, vWF and TLR4 in the thoracic aorta (P<0.05). Conclusion DFMG may inhibit the angiogenesis and maintain the stability of atherosclerotic plaque in the atherosclerotic ApoE-/- mice.