Recent studies indicate beneficial effects of androgen depletion in male mice, before traumahemorrahge on cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Nonetheless, it remains unknown whether androgen receptor blockade following the insult has any salutary effects. To study this, male CSH/HeN mice were either sham-operated or subjected to soft-tissue trauma (i.e., 2.5 cm midline laparotomy) followed by hemorrhagic shock (blood pressure 35 ± 5 mmHg for 90 min) and then adequately resuscitated (shed blood and lactated Ringer's). Immediately after the completion of resuscitation, as well as 24 and 48 h thereafter, the animals received either vehicle, 10 mg/kg body weight (BW) flutamide or 25 mg/kg BW flutamide subcutaneously. At 72 h after resuscitation, all animals were killed. The spleens and peritoneal macrophages (Mφ) were then harvested and cultures established to determine IL-2 and IL-3 release, splenocyte proliferative capacity, as well as splenic and peritoneal Mφ IL-1 release. Moreover, plasma testosterone and corticosterone levels were measured. Our results indicate that trauma-hemorrhage resulted in significant depression of splenocyte and Mφ functions in vehicle-treated and animals receiving 10 mg/kg BW flutamide. Treatment with 25 mg/kg BW flutamide following trauma-hemorrhage, however, resulted in levels of cytokine release which were comparable with those found in sham-operated animals. No significant alterations in plasma corticosterone and testosterone levels were observed in any of the experimental groups. These findings indicate that short-term therapy of males with the androgen receptor blocker, flutamide at 25 mg/kg BW, following trauma-hemorrhage has protective effects on immune functions. This protective effect is dose dependent, since 10 mg/kg BW flutamide did not produce significant salutary effects. Thus, flutamide represents a novel and safe agent for improving the depressed functions in male trauma patients suffering severe blood loss.