In addition to its classic roles in sexual development and function, estrogen (“E2”) is an important immune regulator. The impact of E2 in a given cell is determined by the relative contribution of signaling downstream of two ligand-activated nuclear receptors, estrogen receptors alpha and beta (ERa, ERb), with ERb generally mediating anti-inflammatory effects. Altered ER signaling likely contributes to the female sex bias observed for many autoimmune diseases including Crohn’s disease (CD). We observed reduced ERb expression in inflamed mucosal tissues and peripheral blood T cells from female CD patients, suggesting that reductions in ERb signaling may promote chronic intestinal inflammation in females.