OBJECTIVE To examine the kinetics of altered soluble tumor necrosis factor receptors (sTNFRs) released in patients with severe sepsis, their correlation with the morbidity and mortality of these patients, and the role of endotoxin to induce cleavage of sTNFRs. METHODS Soluble TNFR levels in plasma obtained from 40 patients with severe sepsis (mean [+/- SD] Acute Physiology and Chronic Health Evaluation [APACHE] II score, 27.9 +/- 7.0 points) on days 0, 1, 3, 5, and 10 after sepsis diagnosis were measured using specific enzyme-linked immunological binding assays and compared with levels in 75 control patients without infection. In addition, an ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Blood from patients with sepsis and control patients was incubated in the presence or absence of lipopolysaccharide (1 mg/L) for 0, 1, 2, 4, 8, and 24 hours. Plasma levels of sTNFRs from both groups were determined using the enzyme-linked immunological binding assays. RESULTS In patients with sepsis, plasma levels of both sTNFRs were markedly (P < .01) increased during the whole observation period, compared with those of control patients, and correlated (P < .001) with the simultaneously obtained APACHE II and multiple organ failure scores, as well as with mortality. Although incubation of whole blood with lipopolysaccharide increased the release of sTNFR p55 and p75 in both groups, sTNFR concentrations in blood from control patients remained low compared with those of patients with severe sepsis, despite stimulation of whole blood with a maximum lipopolysaccharide concentration. CONCLUSIONS These data indicate that an enhanced release of sTNFRs during severe sepsis is not solely induced by endotoxin. Since the degree of increased sTNFR levels portended poorly for patient survival, elevated sTNFR levels may represent a good marker for severity of sepsis, thus predicting outcome.