Objectives: Immune functions are markedly depressed in males but not in proestrus females after trauma-hemorrhage. Nonetheless, it is unclear what role sex steroids play in the maintenance of immune function in females after trauma-hemorrhage. Design: Prospective, controlled animal study. Setting: University research laboratory. Subjects: Eight-week-old female CBA/J mice. Interventions: Mice underwent sham-ovariectomy or ovariectomy. Two weeks thereafter, ovariectomized and proestrus sham-ovariectomized mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 ± 5 mm Hg for 90 mins, resuscitated) or sham operation. Splenocyte proliferation and interleukin-2, interleukin-3, and interferon-γ, release were determined at 2 hrs after trauma-hemorrhage. Measurements and Main Results: These immune functional capacities were maintained in proestrus sham-ovariectomized mice after trauma-hemorrhage, whereas they were suppressed in ovariectomized mice subjected to trauma-hemorrhage. 17β-Estradiol in vitro had no effect on splenocyte functions in proestrus sham-ovariectomized females; however, addition of 17β-estradiol to splenocytes from ovariectomized females subjected to trauma-hemorrhage normalized immune functional capacities. Conclusions: These findings suggest that elevated circulating 17β-estradiol in proestrus females plays a direct role in the maintenance of immunocompetence after trauma-hemorrhage.