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Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1beta treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17alpha-Ethinyl estradiol (EE) pretreatment reduced the IL-1beta induction of approximately one third of these genes. Estrogen receptor alpha (ERalpha) was required for this inhibitory activity, because EE inhibition of IL-1beta-stimulated gene expression occurred in ERbeta knockout mice, but not in ERalpha knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-kappaB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1beta gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1beta signaling. Finally, the ability of EE to repress IL-1beta gene induction varied among tissues. For example, EE inhibited IL-1beta induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1beta signaling through a coactivator-based mechanism.