The occurrence of peritoneal adhesions in surgical patients is positively correlated with tumor necrosis factor (TNF) levels. In a model of septic peritonitis-cecal ligation and puncture-TNF neutralization prevented formation of peritoneal adhesions and increased mortality, most likely because localization of the septic focus was prevented. To discriminate between the coagulation-independent protective TNF effect and a potential protective procoagulant TNF effect, formation of peritoneal adhesions after CLP was inhibited with heparin, hirudin, or urokinase. Each treatment increased mortality and increased the number of bacteria in the peritoneal lavage fluid, kidney, and liver to various degrees. Under these experimental conditions, antibiotics prevented death. In coagulation-compromised mice, lethality was further enhanced by additional TNF neutralization. These findings demonstrate that peritoneal adhesions early in septic peritonitis are an important mechanism of innate immunity that prevents increased spread of bacteria and reduces mortality.Although tumor necrosis factor (TNF) was regarded for many years as the major cytokine causing morbidity and mortality in sepsis and septic shock (13), clinical studies testing TNF inhibitors in septic shock did not yield encouraging results (11,30). Besides the many sepsis/septic shock models demonstrating that TNF inhibitors protect animals from bolus injections with lipopolysaccharide (LPS) or bacteria, there are also reports concerning the use of TNF inhibitors in models of bacterial peritonitis where either no effect on survival (1, 10, 23) or even deleterious effects (7) were observed. The observation that mice treated with an anti-TNF monoclonal antibody after cecal ligation and puncture (CLP) show both increased mortality and reduced peritoneal adhesions raised the question of whether survival after CLP depends on adhesions (8). Peritoneal adhesions induced by intestinal bacteria can be inhibited by TNF neutralization (12). In addition to experimental data, after surgical intra-abdominal manipulations in patients, higher grades of adhesions correlated with higher levels of TNF both in serum and peritoneal exudate (15).TNF has procoagulant and antifibrinolytic effects both in blood and on mesothelium (6,26,27). At higher TNF concentrations these properties might lead to disseminated intravascular coagulation (DIC), which is uniformly regarded as harmful during sepsis. Therefore, prevention of coagulation might protect against sepsis (3). Antithrombin III or hirudin, indeed, ameliorated DIC and protected rats against sequelae of intravenous administration of LPS alone or injection of bacteria together with an antibiotic, whereas heparin plus antibiotic had no effect on survival in the latter model. This might be due to the fact that the anticoagulant function of heparin is indirect by accelerating antithrombin III binding to thrombin (4,5,19).The situation in bacterial peritonitis, however, is different since anticoagulant treatment may enhance the spread of bacter...