Refractory pouchitis (RP) is a debilitating complication of ileal pouch reservoirs that affects approximately 2.5% of patients. Although the cause of RP is unknown, it is frequently hypothesized that it reflects underlying Crohn's disease. Since perinuclear anti-neutrophil cytoplasmic antibody (pANCA) is found in approximately 70% of ulcerative colitis patients but only rarely in Crohn's disease patients, it may help distinguish Crohn's disease from ulcerative colitis. Therefore, to test whether RP reflects "missed" Crohn's disease, we determined the ANCA status of 26 patients with RP. The pANCA was positive in 42% of cases [50% of Kock pouch cases and 33% of ileoanal pull-through (IAPT) cases] and 57% of matched control subjects without pouchitis (N = 42, P = NS). Moreover, 3/6 (50%) of IAPT RP subjects whose signs and symptoms most suggested Crohn's disease tested positive for pANCA. When compared to controls, IAPT cases exhibited significantly more preoperative extraintestinal manifestations (EIMs) of inflammatory bowel disease (P < 0.05). The presence of preoperative EIMs was 100% predictive of postoperative EIMs (P < 0.05). Review of pouch biopsies from cases of RP revealed no pathognomonic histologic features of Crohn's disease. These data confirm our previous suggestion that RP does not reflect underlying Crohn's disease but may be associated with the EIMs of inflammatory bowel disease.