Gut mucosal hypoperfusion is associated with a poor outcome following major surgery but the pathogenetic mechanisms remain poorly understood. We have examined the relationship between gut mucosal hypoperfusion, endotoxin core antibodies (EndoCAb), neutrophil elastase alpha-1 antitrypsin complexes (NE) and components of the contact system during elective major surgery. Of the 26 patients studied 16 developed gut mucosal hypoperfusion (pHi < 7.32) by the end of surgery; of these four developed multiple organ failure (MOF) and three subsequently died. In this group there was a significant rise in NE (P< 0.005) and significant reductions in components of the contact system (factor XII, anithrombin III, prekallikrein and C1-inhibitor;P< 0.001) from immediately before surgery to 24h later. Ten patients maintained gut mucosal perfusion (pHi ≥ 7.32); none of these developed life threatening complications. In this group there was no significant increase in NE and, although there were significant reductions in some components of the contact system (P< 0.01), levels of C1-INH were not reduced. All patients demonstrated a significant reduction in both IgG and IgM EndoCAbs (P≤ 0.005) indicating exposure to endotoxin. However, the group that maintained gut mucosal perfusion had significantly higher IgG EndoCAb levels at baseline and 24 h (P≤ 0.005). These data suggest that all patients were exposed to endotoxin and that high levels of anti-endotoxin antibodies may contribute to the prevention of endotoxin-induced contact activation, neutrophil degranulation and gut mucosal hypoperfusion occurring during major surgery and thus reduce the likelihood of the development of post-operative MOF.