The protective effects of 17β-estradiol in cerebral ischemia may be partially due to the blockade of leukocyte adhesion in cerebral endothelial cells, although the molecular mechanisms are not well understood. We report that 17β-estradiol (E2), but not the α-enantiomer, inhibited the basal and interleukin-1β (IL-1β)-mediated expression of the intercellular adhesion molecule type 1 (ICAM1) and NFκB activation, in cultured brain endothelial cells. However, the degradation of IκB-α, which is an essential requirement for the translocation of NFκB to the nucleus, and a common biological target to suppress NFκB activation, was not halted by E2. These findings indicate that decreased expression of adhesion molecules may account for the capacity E2 to reduce adhesion of leukocytes in cerebral endothelium in vivo, and suggest the existence of brain-specific, estrogen-sensitive pathways, other than IκB-α_-regulation, to modulate NFκB. The stereoselectivity of the E2 effect is consistent with an estrogen receptor-mediated mechanism.