Antineutrophil cytoplasmic antibodies (ANCAs) have recently been demonstrated to be of importance in Wegener's granulomatosis and certain other forms of vasculitis associated with glomerulonephritis. With a fixed-cell ELISA, we demonstrated that ANCAs occur in the serum of patients with inflammatory bowel disease (IBD) involving the colon. In a blinded study, sera from 21 of 25 patients with ulcerative colitis (UC) and five of 25 patients with Crohn's disease had binding in the fixed-cell ELISA. The five reactive sera from patients with Crohn's disease were associated with the presence of clear colonic involvement. The presence of ANCA in patients with UC was not influenced by disease distribution or activity. Indeed, such antibodies were present in four subjects with UC more than 5 years after colectomy. The IBD-associated ANCAs were distinct from ANCAs reported in patients with Wegener's granulomatosis since the pattern of staining on indirect immunofluorescence exhibited a nongranular perinuclear distribution (P-ANCA). The P-ANCA observed in IBD did not react with myeloperoxidase and thus was distinct from the P-ANCA observed in vasculitis with cresentric glomerulonephritis. IBD and, in particular, UC, is associated with a distinct subset of P-ANCA, which may have important diagnostic and potential pathophysiologic implications.