While estrogen receptor (ER) profile plays an important role in the response to estrogens, receptor co-regulators act as critical determinants of signaling. Although the clinical effects of ovarian hormones on various normal and pathological processes are an active area of research, the exact signaling effects on, for example the vessel wall, are incompletely understood. Hence, we sought to discover proteins that associate with ER, the isoform that shows up- regulated mRNA expression after arterial injury. Using a yeast two hybrid screen we identified NM23-H2, a multi-faceted metastasis suppressor candidate protein, as an ER associated protein. Although NM23-H2 was immunodetected in arteries from young subjects (27±6 years, 14 males and 6 females) with benign intimal hyperplasia, expression was diminished in fatty streaks/ atheromas, and altogether absent in advanced atherosclerotic lesions. Both nm23-H2 mRNA and protein were expressed by vascular cells in vitro. Treatment with 17-estradiol and an ER-selective agonist, DPN, increased protein expression of NM23-H2; an effect that was not seen with an ER selective agonist, PPT. Estrogen also prompted nuclear localization of NM23-H2 protein in human coronary SMCs. An in vitro mimic of inflammation decreased the expression of NM23-H2 in SMCs, which was restored upon addition of estrogen and dependent upon the estrogen receptor. In summary, we report the novel association of NM23-H2 with ER, and show for the first time its expression in vascular cells and demonstrate regulation of its expression and localization by estrogen. In that the abundance of NM23-H2 diminishes with both the advancement of atherosclerosis and inflammation, this ER associated protein may play an important role in mediating the vasculoprotective effects of estrogens.