Lipid A is a component common to endotoxins of gram-negative bacteria. It has been suggested that the gut wall of patients with inflammatory bowel disease is more permeable to luminal bacterial macromolecules which may stimulate the gut-associated lymphoid tissue. We therefore investigated 40 patients with Crohn's disease (CD) and 23 patients with ulcerative colitis (UC) with respect to their lipid A antibody titers and presence of endotoxins (Limulus test). Both tests were performed simultaneously using peripheral venous blood. Systemic endotoxin was demonstrated in only two of the patients. The lipid A antibody titers in the CD patients were significantly higher than either in patients with UC or in 42 healthy controls. Lipid A titers of patients with UC did not differ from those of controls. Titers of lipid A were significantly higher in patients with active Crohn's disease than in patients with inactive disease. It is concluded that systemic endotoxemia occurs rarely in patients with inflammatory bowel disease; however, despite this virtual absence of endotoxins in their peripheral blood, patients with CD show an increase in antibody formation against lipid A. This is suggestive of an altered immunologic reactivity against endotoxins in patients with CD and may be relevant to the pathogenesis of this disease.