The atheroprotective effects of estrogen in women are well recognized¹, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ERα (ref. 2—6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions⁷⁸. We have generated mice in which the ERα gene is disrupted⁹ and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17β-estradiol. Suprisingly, in both wild-type and estrogen receptor-deficient mice, 17β-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular injury by a novel mechanism that is independent of the classic estrogen receptor, ERα.