Kupffer cells are macrophages in the liver whose major role is to clear circulating pathogens. Decreased phagocytic capacity of Kupffer cells may result in severe systemic infection. We tested the hypothesis that the depressed Kupffer cell phagocytic capacity following trauma-hemorrhage is enhanced by estrogen administration and this occurs due to maintenance of Fc receptor expression and cellular ATP content via the activation of Akt. Male C3H/HeN mice were subjected to sham operation or trauma-hemorrhage and sacrificed 2 h thereafter. Estrogen, with or without an estrogen receptor antagonist (ICI 182,780), a PI3K inhibitor (Wortmannin), or vehicle, was injected during resuscitation. Kupffer cell phagocytic capacity was tested in vivo. The expression of Fc receptors, of Akt phosphorylation, of p38 MAPK phosphorylation, of DNA binding activity of NF-κB and ATP content of Kupffer cells were also determined. Trauma-hemorrhage suppressed Kupffer cell phagocytosis by decreasing Fc receptor expression and Akt activation; however, it induced p38 MAPK activation and increased NF-κB activity. Cellular ATP levels were also decreased following trauma-hemorrhage. Administration of estrogen following trauma-hemorrhage increased phospho-Akt levels and normalized all the parameters described as well as plasma levels of TNF-α, IL-6, and IL-10. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of estrogen in improving the phagocytic capacity of Kupffer cells following trauma-hemorrhage. Thus, activation of Akt plays a crucial role in mediating the salutary effect of estrogen in restoring trauma-hemorrhage-induced suppression of Kupffer cell phagocytosis. Copyright © 2009 by The American Association of Immunologists, Inc.