Aim and Background The beneficial effect of estrogen on atherosclerosis and related cardiovascular disease has been recognized, however there were obvious adverse side effect recently. This controversy were continued more intensely. We found a new phytoestrogen α-Zearalanol (ZAL). Our lab first brought ZAL into medical research field to study its antiatheorsclewsis effect. To examine the effect on atherosclerosis (As) development and serum lipid prolife, and in comparison with estrogen, in order to provide a basic materials for future study. Methods Sixty adult female New-Zealand rabbits were divided into 7 groups: normal control (NC)group (n=6), sham-operated (SO) group (n=8),high-cholesterol control(HCC) group (n=10), small dose ZAL (SDZ) group (n=8), medium dose ZAL (MDZ) group (n=10),large dose ZAL (LDZ) group (n= [WT5”BZ]8), 17β-estrogen (E₂) group (n=10). All groups except NC group and SO group were treated with oophoretomy; all groups except NC group were fed with high-cholesterol for 12 weeks. At week 0, 4, 8, and 12,the serum lipid TC, TG, HDLC, LDLC, apolipoprotein Al and B were measured. At feeding cholesterol week 12 the area of aortic intima lipid plagues to total area of aortic intima were evaluated by scanner and the pathologic changes were observed. Results The ratio of area of aortic lipid plaque to total area of aortic intima in NC group was 0.02±0.003, in SO group was 0.42±0.15, in HCC group was 0.67±0.23, in SDZ group was 0.61±0.13, in MDZ group was 0.10±0.06, in LDZ group was 0.32±0.10, in E₂ group was 0.12±0.11 (SO group, MDZ group, LDZ group, and E₂ group four groups are compared with HCC group,p<0.01). The serum contents of TC, TG, LDLC, apolipoprotein B in HCC group was siginificantly increased compared with the SO group, while those in MDZ groups, LDZ group, and E₂ group, were significantly decreased compared with HCC group. The pathologic changes showed in NC group intact endothelial cell. In HCC group it showed severe endothelial cell damaging and falling off, liquid like necrosis, obvious outward shifting of intimal elastic layer, a large amount of foam cell and lipid plaque, necrosis and calcification. In SO group, in MDZ groups, LDZ group, and E₂ group, aforementioned pathological atteration were significantly attenuated. Conclusion Administration of ZAL can decrease the area of aortic lipid plaque and markedly reduce the pathological changes and participate improvement and regulation of disturbance of lipid metabolism including the degree on hyperlipidemia. Phytoestrogen ZAL has a potentially importment antiatherogen effect. Analogous to that observed with 17β-estrogen in this model.