Cyclooxygenase inhibitors improve systemic hypotension, cardiac output, and metabolic acidosis in endotoxemia. However, the capacity of cyclooxygenase inhibitors to increase survival in a bacteremic animal model of injury has been inadequately addressed. This study evaluated the potential of a single intravenous dose of ibuprofen, a reversible cyclooxygenase inhibitor, to effect changes in cardiovascular variables and survival in unanesthetized sheep given live E. coli and antibiotic therapy. We found that ibuprofen significantly improved survival in this model with 66% survival in sheep treated with ibuprofen compared to 0% survival in sheep not treated with ibuprofen. Sheep treated with ibuprofen were protected against the drop in mean arterial pressure and increase in heart rate observed in sheep that received E. coli and antibiotics. Pulmonary arterial pressure and pulmonary capillary wedge pressure values were lower in animals treated with ibuprofen than values of animals that did not receive ibuprofen. Bacteremic rats treated with ibuprofen exhibited similar increased survival over that of untreated controls; this survival advantage was not demonstreted with indomethacin. These data show increased survival in septic sheep and rats with the administration of 10 mg/kg intravenous ibuprofen, and suggest that lessened systemic hypotension and pulmonary hypertension may contribute to the therapeutic effect of ibuprofen treatment.