Astroglial reactivity associated with increased production of NFκB-dependent proinflammatory molecules is an important component of the pathophysiology of chronic neurological disorders such as multiple sclerosis (MS). The use of estrogens as potential anti-inflammatory and neuroprotective drugs is a matter of debate. Using mouse experimental allergic encephalomyelitis (EAE) as a model of chronic neuroinflammation, we report that implants reproducing pregnancy levels of 17β-estradiol (E2) alleviate ongoing disease and decrease astrocytic production of CCL2, a proinflammatory chemokine that drives the local recruitment of inflammatory myeloid cells. Immunohistochemistry and confocal imaging reveal that, in spinal cord white matter EAE lesions, reactive astrocytes express estrogen receptor (ER)α (and to a lesser extent ERβ) with a preferential nuclear localization, whereas other cells including infiltrated leukocytes express ERs only in their membranes or cytosol. In cultured rodent astrocytes, E2 or an ERα agonist, but not an ERβ agonist, inhibits TNFα-induced CCL2 expression at nanomolar concentrations, and the ER antagonist ICI 182,170 blocks this effect. We show that this anti-inflammatory action is not associated with inhibition of NFκB nuclear translocation but rather involves direct repression of NFκB-dependent transcription. Chromatin immunoprecipitation assays further indicate that estrogen suppresses TNFα-induced NFκB recruitment to the CCL2 enhancer. These data uncover reactive astrocytes as an important target for nuclear ERα inhibitory action on chemokine expression and suggest that targeting astrocytic nuclear NFκB activation with estrogen receptor α modulators may improve therapies of chronic neurodegenerative disorders involving astroglial neuroinflammation.