Endothelin is the most potent vasoconstrictor peptide known to date. Hormone replacement therapy (HRT) with estrogen reduces plasma endothelin levels. We measured endothelin in 51 postmenopausal patients before and during HRT. Patients were randomly allocated to receive either oral tibolone, oral or transdermal 17 beta-estradiol. A group of comparable volunteers served as controls. After 24 months, endothelin levels decreased in all treatment groups: tibolone, 18.2%; oral 23.1%; transdermal, 20.8%. Endothelin levels increased in the controls by 36.6% (p < 0.01). Tibolone decreases endothelin levels to a similar degree as conventional estrogen-progestogen-replacement therapy. These data provide another potential mechanism supporting the cardioprotective effects of tibolone.