Objective: To determine whether closed bone fracture in conjunction with hemorrhagic shock compromises immune functions more severely than hemorrhagic shock alone. Design: In a randomized, controlled trial, closed bone fracture of the right lower leg and/or hemorrhagic shock (mean±SEM arterial blood pressure, 35±5 mm Hg for 90 minutes) were induced in male C3H/HeN mice (weight, 25 g). Animals subjected to hemorrhage were resuscitated with the shed blood and lactated Ringer solution. At 72 hours after the experiment, all animals were killed to obtain whole blood, splenocytes, and splenic and peritoneal macrophages. Macrophage interleukin-1 and splenocyte interleukin- 2 and interleukin-3 release were determined by bioassay, and splenocyte proliferation was measured by tritiated thymidine incorporation. Results: Closed bone fracture alone did not affect immune functions 72 hours after the trauma. Hemorrhagic shock, however, induced a significant depression of splenocyte and macrophage functions. Bone fracture followed by hemorrhagic shock further depressed splenocyte proliferation and splenocyte interleukin- 2 and interleukin-3 release as well as interleukin-1 release. Conclusion: Since bone injury coupled with hemorrhagic shock produces more severe depression of immune functions than hemorrhage alone, bone injury appears to play a contributory role in further depressing immune functions in trauma patients who experience major blood loss.