Although hemorrhage or trauma (laparotomy) alone in mice produces a marked immunosuppression for 3 to 4 days and trauma plus hemorrhage produces immune depression for 5 days after resuscitation, it remains unknown when the immune functions return to normal after trauma-hemorrhage and whether lymphocyte and macrophage functions are similarly affected by trauma-hemorrhage. Male C3H/HeN mice underwent either sham operation, trauma (laparotomy), hemorrhagic shock (mean arterial blood pressure of 35 +/- 5 mm Hg for 60 minutes, followed by fluid resuscitation), or trauma plus hemorrhage. Plasma, splenocytes, splenic macrophages, and peritoneal macrophages were harvested at 7 or 10 days after the operation. Plasma and macrophage tumor necrosis factor, interleukin (IL)-6, and splenocyte IL-2 and IL-3 release were determined by bioassay, and splenocyte proliferation was measured by [3H]thymidine incorporation. Splenocyte proliferation, splenocyte lymphokine release, and splenic and peritoneal macrophage cytokine release were still markedly decreased in the trauma-hemorrhage group compared with other groups at 7 days but returned to normal by day 10. Tumor necrosis factor and IL-6 levels, however, were not detectable in plasma of any groups at 7 or 10 days after operation. The results indicate that a more severe and prolonged immunodepression occurs after combined trauma and hemorrhage than after trauma or hemorrhage alone.