Since splenic immune functions are depressed in metestrus females following trauma-hemorrhage, we hypothesized that administration of the androgen receptor antagonist flutamide at the onset of resuscitation will maintain the immune function of the spleen following trauma-hemorrhage. Female C57BL6/J mice (metestrus state, 8-12 weeks old), underwent laparotomy and hemorrhagic shock (35.0 ± 5.0 mm Hg for 90 min) and received 17β-estradiol (50 μg/25 g), flutamide (625 μg/25 g) or 17β-estradiol + flutamide. Four hours after resuscitation, the in vitro productive capacity of different cytokines (TNF-α, IL-6, IL-10, and IFN-γ) by splenic MΦ and splenocytes were determined by flow cytometry. A significantly decreased cytokine production by both splenocytes and splenic MΦ was observed following trauma-hemorrhage compared to shams. Administration of 17β-estradiol, flutamide and 17β-estradiol + flutamide following trauma-hemorrhage resulted in a significant increase in the in vitro IL-6 release by splenic MΦ. The TNF-α productive capacity, however, was only restored by 17β-estradiol and 17β-estradiol + flutamide administration following trauma-hemorrhage. No significant effect of either treatment was observed with regard to the suppressed splenic MΦ IL-10 release. Anti-CD3 stimulation, administration of 17β-estradiol and 17β-estradiol + flutamide, but not the administration of flutamide alone resulted in a significant increased release of TNF-α, IL-6 and IFN-γ compared to vehicle-treated animals. No significant effect of either treatment was found on IL-10 productive capacity. These results collectively suggest that flutamide administration following trauma-hemorrhage in females has beneficial effects on splenic immune function. However, flutamide administration in combination with estrogen does not provide any significant, additional effects over 17β-estradiol administration alone. © 2007.