Although favorable effects of estrogen replacement therapy on atherosclerosis have been recognized, the benefit versus risk of estrogen replacement on overall cardio- vascular health remains controversial. The main adverse effect jeopardizing the clinical usage of estrogen is the increased risk of breast and endometrial cancer. Zearalenone (ZEN) is a universal endogenous hormone possessing estrogen-like effects and facilitating plant growth. alpha-Zearalanol (alpha-ZAL), a new phytoestrogen, is a reductive product of ZEN. Our preliminary evidence suggested that alpha-ZAL is anti-atherosclerotic. The aim of this study was to examine the effect of alpha-ZAL on atherosclerotic formation and serum lipid profile. Adult female nulliparous rabbits were ovariectomized or sham-operated and fed a high-cholesterol diet with different doses of alpha-ZAL or 17beta-estradiol for 12 wk. The aortic intimal atherosclerotic plaque was significantly larger in the cholesterol-fed group compared to control and sham groups. alpha-ZAL and 17beta-estradiol treatments significantly reduced plaque formation and improved serum profile of lipid (TC, TG, HDL-C, and LDL-C) and lipoprotein (ApoAl and ApoB). Both alpha-ZAL and 17beta-estradiol reconciled ovariectomy-induced uterine atrophy, although alpha-ZAL was significantly less potent than 17beta-estradiol in stimulating uterine growth. Our findings indicate that the phytoestrogen alpha-ZAL has an important anti-atherogenic property, analogous to that of estrogen.