Evidence of a humoral immune response to endothelium was sought in the sera of patients with inflammatory bowel disease. In an ELISA, IgG binding to human umbilical vein endothelial cells was found in 21% of Crohn's disease sera, 10% of ulcerative colitis sera, 6% of sera from patients with acute infective diarrhea, and 8% of normal control sera. The increased prevalence in Crohn's disease sera was significant (P < 0.05). IgG-endothelial cell binding was cell specific, was not Fc-mediated, and did not mediate complement-dependent cell lysis. It was not increased by pretreatment of cells with interleukin-1 or tumor necrosis factor. Endothelial cell binding was retained by IgG F(ab')2 fragments from one of three reactive Crohn's sera, but none of three nonreactive sera. The low prevalence of this interaction, even in patients with immunohistochemically confirmed vasculitis, makes it unlikely that Crohn's disease is determined by a humoral autoimmune response to endothelium.