Endotoxins have been suggested to be a factor in the pathophysiology of Crohn's disease (CD). We determined circulating antibodies against lipid A, a component common to endotoxins of gram-negative bacteria. Lipid A antibody titers in 91 patients with CD were significantly higher than in 56 patients with ulcerative colitis and 68 healthy subjects. In active CD lipid A antibodies were higher than in quiescent CD and markedly elevated titers of lipid A antibodies were associated with a severe course of CD. Duration, extent and localisation of CD showed no relationship to antibody titers against lipid A. Patients with prior bowel resection had a tendency towards lower antibody titers in comparison with non-operated patients. After total removal of inflamed bowel tissue, lipid A antibodies frequently disappeared. Medical therapy had different effects: prednisone and sulfasalazine did not influence antibody formation against lipid A, whereas antibody titers dropped significantly after therapy with ampicillin. These results confirm elevated circulating lipid A antibodies in patients with CD. Although it remains unclear whether lipid A antibodies are only an epiphenomenon in CD, on the basis of this clinical study further evidence is provided for the involvement of lipid A in the pathophysiology of CD.