The production and clearance of tumor necrosis factor (TNF) in relation to endotoxinemia was studied by the injection of lipopolysaccharide (LPS) in rats. TNF was released into the circulation as a burst when the serum concentration of LPS was rapidly or gradually increased. The maximum concentration of TNF in serum was attained 60 to 90 min after the injection of LPS. TNF was eliminated from the serum according to a first-order kinetics; the half-life was calculated to be 27 +/- 7 min. No additional release of TNF could be evoked by a persistent high level of LPS. When two LPS injections were given within 3 days, the peak concentration of TNF detected after the second injection was 15% of the concentration detected after the first injection. The results indicate that if TNF is a mediator of septic shock, its role is restricted to the initial phase after the appearance of endotoxin in the circulation. Treatment of the rats with dexamethasone (0.5-2.0 micrograms/g) reduced the LPS-induced peak concentrations of TNF in serum by 70-90%. Maximal suppression of the TNF release was observed when dexamethasone was given 5 hr or more prior to LPS, but was gradually lost at shorter intervals.