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Chronic diarrhea is a relatively common condition with multiple diverse etiologies. Stool testing may serve as a diagnostic aid to discriminate the presence or absence of organic pathology, such as colorectal inflammation. Calprotectin (a leukocyte-derived protein) and hemoglobin can be measured quantitatively from stool and represent candidate inflammation biomarkers. The aim of this study was to assess and compare the screening performance of fecal calprotectin and fecal hemoglobin among colonoscopy referral patients with chronic diarrhea of unknown origin or chronic colitis of unknown activity.All subjects were identified prospectively and each submitted a single stool sample before purgation. Fecal calprotectin (PhiCal; Nycomed Pharma, Oslo, Norway) and fecal hemoglobin (HemoQuant; Mayo Medical Laboratories, Rochester, MN) assays were performed in separate laboratories by masked technicians. Colonoscopic and histological findings served as criterion standards for establishing the presence or absence of colorectal inflammation.Among 110 subjects who provided complete fecal assay data, 29 (26%) had and 81 (74%) did not have colorectal inflammation. Increased fecal calprotectin levels were significantly (p = 0.0001) associated with the presence of colorectal inflammation, whereas fecal hemoglobin levels were not (p = 0.61). Direct comparison of the fecal assays revealed that calprotectin was a more sensitive biomarker for colorectal inflammation at all specificity levels (p = 0.0001).In this study of colonoscopy referral patients, colorectal inflammation was reflected by fecal calprotectin but not by fecal hemoglobin levels. Assay of fecal calprotectin holds promise as a triage tool to identify inflammatory causes of chronic diarrhea.