Neutrophil infiltration is a key step in the development of organ dysfunction following trauma-hemorrhage. Although we have previously shown that 17-estradiol prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which 17-estradiol inhibits neutrophil transmigration remains unknown. We hypothesized that 17-estradiol prevents neutrophil infiltration via modulation of keratinocyte-derived chemokine (KC), a major attractant for neutrophils. To examine this, male C3H/HeN mice were subjected to trauma-hemorrhage or sham operation and thereafter resuscitated with Ringer lactate and 17-estradiol (1 mg/kg body weight) or vehicle. Animals were sacrificed two hours after resuscitation and Kupffer cells were isolated. Plasma levels and Kupffer cell production capacities of KC, TNF- and IL-6 were determined by BDTM Cytometric Bead Arrays; lung mRNA expression of KC was measured with real time PCR; myeloperoxidase activity assays were performed to determine neutrophil infiltration and organ damage was assessed by edema formation. Treatment with 17-estradiol decreased systemic levels and restored Kupffer cell production of KC, TNF- and IL-6 as well as KC gene expression and protein in the lung. This was accompanied with a decrease in neutrophil infiltration and edema formation in the lung. These results suggest that 17-estradiol prevents lung neutrophil infiltration and organ damage in part by decreasing KC during posttraumatic immune response.