The prostaglandins are potent vasoactive fatty acids that are ubiquitously distributed throughout the body. It is now well established that the prostaglandins participate in a variety of pathophysiological processes such as inflammation, burns, renal aspects of hypertension, peptic ulcer disease, diarrhea, skin conditions, vasomotor dysfunctions, platelet abnormalities, dysmenorrhea, fever, and shock. We have previously shown that the prostaglandins appeared to be elevated and were related to the circulatory dysfunction in canine and baboon endotoxin shock. In addition, our studies demonstrated that indomethacin, a prostaglandin synthetase inhibitor, not only inhibited the prostaglandin release and improved the hemodynamic derangements, but also significantly improved the survival. Indomethacin clearly improved the survival in baboon endotoxin shock even when administered after shock had occurred. Since the previous studies were in endotoxin models, the next logical step was to determine the effects of indomethacin in a clinically-relevant rat sepsis model. Two hundred sixty-six male rats (250-500 g) were randomly allocated to saline treated controls or to indomethacin treatment. A pure suspension of live E. Coli organisms (225 X 10(10)/rat) were injected i.p. to each rat. Treatment was introduced at three hours when all blood cultures were positive. Groups were divided into gentamicin (4 mg/kg/rat) alone, gentamicin and indomethacin (3 mg/kg), or indomethacin alone in addition to the saline treated controls. Results showed that indomethacin in combination with gentamicin significantly (p = 0.05) improved the survival at 24 (90%) and 48 hours (90%), when compared with saline treated controls (65%, 45%) and with gentamicin (40%, 40%). Indomethacin alone significantly (p = 0.01) improved the survival. Conclusions are that (i) therapeutic doses of indomethacin or gentamycin clearly improved the survival in a clinically relevant rat sepsis model; (ii) the exact mechanism of protection with indomethacin is unknown; and (iii) indomethacin should be considered for use in human clinical sepsis.