OBJECTIVES: Fecal lactoferrin (FL) is a non-invasive marker, able to distinguish between inflammatory and non-inflammatory causes of symptoms in patients with ileal pouch-anal anastomosis (IPAA). We assessed the cost-effectiveness (CE) of the FL assay as the initial screening test for the evaluation of symptomatic patients with IPAA. METHODS: The frequencies of pouchitis, irritable pouch syndrome, cuffitis, and Crohn's in symptomatic patients were estimated to be 50%, 36%, 7%, and 7% respectively. The FL assay has a sensitivity of 100% and a specificity of 85% (7mg/ml threshold) to distinguish between inflammatory and non-inflammatory causes of symptoms. Four competing diagnostic strategies [empiric metronidazole therapy (txMTZ), initial pouch endoscopy/biopsy (testBiop), initial FL assay then MTZ when warranted (testFL + MTZ), and FL assay then pouch endoscopy/biopsy when warranted (testFL + Biop)] were modeled in a decision tree. Response rates to all therapies were based on current literature and expert opinion. Effectiveness equaled the number of days out of 30 that a patient received responsive therapy. Procedural and drug costs were estimated from the 2003 Medicare fee schedule and current average wholesale price, respectively. RESULTS: In the base case, the average cost per patient was $244 for testFL + MTZ, $251 for txMTZ, $408 for testFL + Biop, and $431 for testBiop. All competing strategies were more effective than test FL + MTZ, with incremental effectiveness ranging from 2.0 to 0.1 days at an incremental cost ranging from $8 to $1263. The incremental CE ratio for txMTZ and testFL + MTZ of only $8 does not reflect unnecessary antibiotic exposure resulting in delayed diagnosis, adverse effects, antimicrobial resistance, or patient preference for the 50% relative decrease in invasive endoscopic procedures. Results were robust in multivariate sensitivity analyses. CONCLUSIONS: FL measurement prior to treatment with MTZ is a less costly strategy with only a marginal decrease in effectiveness when compared to empiric antibiotic therapy and other diagnostic strategies.