Background: 17β-estradiol (E2) administration following trauma-hemorrhage (T-H) attenuates the elevation in plasma cytokines and Kupffer cell (KC) cytokine production; however, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-α or ER-β. We hypothesized that E2 mediates its salutary effects via ER-α and normalization of MAPK under those conditions. Methods: Male rats underwent T-H (mean blood pressure [BP] 40 mmHg for 90 min) and fluid resuscitation. ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), E2 (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, KCs were isolated and their cytokine production (IL-6, TNF-α, IL-10) and MAPK activation were measured. Results: Cytokine production increased after T-H, however, PPT or E2 administration after T-H normalized KC cytokine production. Although DPN attenuated increased production of these cytokines, KC capacity to produce the cytokines remained significantly higher than sham. PPT or E2 also prevented T-H-mediated activation of MAPK in KC. However, DPN did not prevent MAPK activation. Conclusions: Since PPT administration after T-H was more effective in decreasing KC cytokine production and MAPK activation than DPN, the salutary effects of E2 on KC functions are mediated predominantly via ER-α and normalization of MAPK following T-H. © 2006 Mosby, Inc. All rights reserved.