Background/Aims: The aim of this study was to determine which of the estrogen receptor (ER) subtypes plays a predominant role in ameliorating hepatic damage following trauma-hemorrhage. Methods: Adult male rats were subjected to hemorrhagic shock (40 mmHg for 90 min) and resuscitation. ER-α agonist (PPT) or ER-β agonist (DPN) was administered during resuscitation; rats were sacrificed 24 h thereafter. Results: PPT or DPN decreased elevated plasma α-glutathione S-transferase levels; however, PPT was more effective. PPT or DPN increased hepatic heat shock protein 32 (Hsp32) mRNA/protein expressions above levels observed after trauma-hemorrhage. PPT reduced hepatic NF-κB and AP-1 activity and iNOS expression. Although DPN reduced hepatic NF-κB activity, AP-1 activity remained higher than in shams; hepatic iNOS induction remained elevated. PPT/DPN reduced nitrate/nitrite production and iNOS mRNA in Kupffer cells following trauma-hemorrhage; however, these levels in DPN-treated animals remained higher than sham. Conclusions: Although both PPT and DPN decreased hepatic injury following trauma-hemorrhage, ER-α agonist PPT appears to be more effective in downregulating NF-κB and AP-1 activity, and iNOS induction. Thus, ER-α appears to play a predominant role in mediating the salutary effects of E2 in ameliorating hepatic damage following trauma-hemorrhage. © 2007 European Association for the Study of the Liver.