Background & aims : Increased stool frequency, urgency, and abdominal pain in patients with ileal pouch-anal anastomosis (IPAA) may be due to inflammatory conditions, including pouchitis, cuffitis, or Crohn’s disease or noninflammatory conditions such as irritable pouch syndrome. Distinction among these entities requires pouch endoscopy and biopsy. Noninvasive means of diagnosis are preferable. Methods : Sixty consecutive subjects with IPAA for inflammatory bowel disease had measurements of fecal lactoferrin and α1-antitrypsin and underwent pouch endoscopy with biopsy, with calculation of the pouchitis disease activity index in a prospective cross-sectional study. Results : Symptomatic patients with an inflammatory condition had significantly higher fecal lactoferrin concentrations (median, 176.0 μg/mL, interquartile range [IQR] 79.0–450.8) compared with those with a noninflammatory condition (median, 4.8 μg/mL; IQR, 1.2–11.0) or those who were asymptomatic (median, 7.8 μg/mL; IQR, 1.4–12.9), P < 0.001. At a cutoff level of 7 μg/mL, fecal lactoferrin could distinguish patients with irritable pouch syndrome from those with pouchitis, cuffitis, or Crohn’s disease with a sensitivity of 100% and specificity of 85%. Fecal α1-antitrypsin was not able to distinguish symptomatic patients with and without an inflammatory condition. Conclusions : Fecal lactoferrin can serve as a sensitive and noninvasive initial screening test in an algorithm for evaluation of symptomatic patients with IPAA. If fecal lactoferrin levels are low (<7 μg/mL), IPS can be diagnosed. If fecal lactoferrin levels are high, pouch endoscopy with biopsy is warranted to distinguish among different causes of inflammation. Longitudinal studies are needed to define better the role of this test in the management of patients with IPAA.