Major injury leads to impaired immune responses and increases the risk of infectious complications. Following trauma, increased prostaglandin E2 (PGE2) levels may be important in immunodysregulation. We hypothesized that blocking PGE2 with NS-398, a selective COX-2 inhibitor, during the first 24 h after injury may modify the immune response and protect the host from a subsequent septic challenge. BALB/c mice were given NS-398 (10 mg/kg) immediately after injury, at 12, and at 24 h after sham injury or trauma (femur fracture and 40% hemorrhage). On day 7 after injury, splenic macrophages were evaluated for cytokine production and COX-2 mRNA. In a separate study mice were injured, then given 3 doses of NS-398. After 7 days, cecal ligation and puncture was performed and mice were followed for survival. Traumatized mice given NS-398 had a significant survival advantage compared with trauma mice alone (P < 0.001). Macrophages from traumatized mice showed increased COX-2 mRNA and proinflammatory cytokines compared with controls (P < 0.05), whereas treatment of injured mice with NS-398 significantly decreased proinflammatory cytokine production (P < 0.05) and COX-2 mRNA. Therefore NS-398 given within 24 h of injury suppressed PGE2 through inhibition of cyclooxygenase, in addition to decreasing proinflammatory cytokines, and providing a survival advantage to the host.