Gram-negative sepsis and septic shock continue to be a common cause of death in the intensive care unit in spite of potent antimicrobial agents and supportive critical care treatments. Other investigators have found benefit in the pretreatment of animals with anti-inflammatory agents before the initiation of sepsis or endotoxemia. In contrast, few workers have studied the more clinically relevant outcome of animals given anti-inflammatory agents hours after the onset of sepsis or endotoxemia. We compared the effects of a variety of anti-inflammatory drugs on survival in a clinically relevant murine model of E. coli sepsis and in a separate model of murine endotoxemia. In the model of E. coli sepsis, 8-10 week old 18-22 gram BALB/c mice were given 0.6-0.9 × 109 cfu of E. coli O111 (ATCC 33780) intravenously (I.V.). Amikacin 0.3 mg intraperitoneally (I.P.) was given 3, 24, 48, and 72 hours after bacterial challenge. Three hours after bacterial challenge, mice were given I.V. Ibuprofen and/or WEB 2170, a platelet-activating factor (PAF) inhibitor. Mice were then observed for 7 days. WEB 2170 at 2 mcg/mouse IV did not reduce mortality compared with controls (9/13 vs. 10/11, respectively). Ibuprofen at 200 or 2000 mcg/mouse did not reduce and may have increased mortality. When WEB 2170 and Ibuprofen were administered simultaneously, mortality was identical to controls. In the model of endotoxemia, mice were given 200-250 mcg of E. coli O111 endotoxin I.P. Three hours later 20 or 200 mcg WEB 2170 was administered I.V. with mortalities of 6/9 and 4/5, respectively, vs. controls of 10/11. Ibuprofen 200 mcg I.V. given 3 hours after endotoxin challenge resulted in a mortality of 5/5 mice. Treating mice 1 hour after endotoxin challenge with the simultaneous administration of 20 mcg WEB 2170 + 200 mcg Ibuprofen + 0.05 ml anti-CD11b antibody resulted in a mortality of 5/5 mice. In conclusion, treatment of mice with a platelet-activating factor antagonist or a cyclooxygenase inhibitor or an anti-integrin monoclonal antibody after the onset of sepsis or endotoxemia does not improve survival. These findings are in contrast to the outcomes of animals pretreated with anti-inflammatory agents before the onset of disease. Further investigation using other anti-inflammatory agents singly or in combination after the onset of sepsis or endotoxemia may be warranted.