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Introduction In total, 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor α (ERα) via 2 activation functions, AF1 and AF2, and can also activate membrane ERα. Objective and method Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. Results Whereas the increase in NO production and the acceleration of endothelial healing in response to E2 were abrogated in ERaC451A mice, the protection against atheroma, neointimal hyperplasia, angiotensin II-induced hypertension, as well as the flow-mediated arteriolar remodelling, were preserved. In contrast, these last four beneficial vascular effects were lost in ERαAF20 mice in response to E2. In line with these results, selective activation of nuclear ERα with estetrol (E4) was capable of inducing arterial protection, except for the increase in NO production and the acceleration of endothelial healing. Conclusion Altogether, these results reveal a prominent role for nuclear ERα in the vasculoprotective action of estrogens. This will have major implications in medicine, since the selective nuclear ERα agonist, estetrol, is currently developed as a new oral contraceptive, and as hormone replacement therapy in menopausal women.