Objective: To determine the contribution of soft-tissue trauma plus hemorrhage, bone fracture and hemorrhage, as well as the contribution of bone fracture, soft-tissue trauma and hemorrhage on host immune function. Subjects: Adult male mice (n = 6/group). Design: Prospective, randomized, controlled study. Setting: Animal laboratory at a university-affiliated hospital. Interventions: Closed-bone fracture (right lower leg; external fixation) and/or soft-tissue trauma (2.5-cm midline laparotomy, closed in two layers) were induced before hemorrhagic shock (mean arterial blood pressure of 35 ± 5 (SEM) mm Hg for 90 mins, followed by fluid resuscitation) in male C3H/HeN mice and the animals were killed at 72 hrs after initiation of the experiment. Measurements and Main Results: Splenocyte interleukin (IL)-2 and IL-3 release capacity, as well as splenic and peritoneal macrophage IL-1 and IL-6 release capacity were determined. Different traumatic insults, i.e., bone fracture or soft-tissue trauma in conjunction with hemorrhage, produced comparable immune depression. More significant depression of splenocyte IL-2 and IL-3 release capacity as well as macrophage IL-1 and IL-6 release capacity occurred with the combined insult (i.e., bone fracture/soft-tissue injury and hemorrhage) than after bone injury or tissue trauma alone with hemorrhage. Conclusions: The combination of closed-bone fracture and soft- tissue trauma before hemorrhage leads to even more compromised immunity than either soft-tissue trauma or closed-bone fracture along with hemorrhage. The markedly depressed immune function following bone injury, soft-tissue trauma, and hemorrhagic shock may contribute to the increased susceptibility of severely injured patients to sepsis and the ensuing multiple organ failure in the clinical situation.