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Endotoxemia and gram negative sepsis remain a clinically important problem since mortality rate is still high in these diseases. Recently, the participation of some new potential mediators in this pathology is beginning to be demonstrated but the results obtained on animal models with specific inhibitors are contradictory. In order to clarify the pathological importance of icosanoids and PAF-acether in the septicemic process, we investigated the effects of indomethacin (IND) a cyclooxygenase inhibitor, NDGA and EP 10045 two lipoxygenase inhibitors, dexamethasone (DXM) a phospholipase A2 inhibitor and BN 52021 a PAF-acether receptor antagonist, on the Salmonella enteritidis-induced endotoxic shock (E.S.) in the rat. Injected subcutaneously 15 min before the test, NDGA, EP 10045 and IND were moderately effective when DXM completely prevented the endotoxin lethality. BN 52021 decreased the death rate in a dose-related manner and exerted at a non-active dose a synergistic effect on IND treatment. Furthermore, given orally 1 hour before endotoxin, it provided a potent protective effect. Our results seem to confirm that PAF-acether exerted alone, or in conjunction with products of the cyclooxygenase pathway, a key role in E.S. when LTs seem to play a role of minor importance.