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Background & Aims Histologic recovery of patients with ulcerative colitis (UC) often is incomplete, even among those in clinical and endoscopic remission. Persistent active microscopic inflammation is associated with an increased risk of relapse and colorectal neoplasia. A high level of fecal calprotectin (FC) is a reliable marker of endoscopic lesions in patients with UC. We evaluated the accuracy of FC in identifying patients with UC in clinical and endoscopic remission who still have histologic features of inflammation. Methods We performed a prospective observational study of 59 patients with UC in clinical and endoscopic remission undergoing colonoscopy. Several biopsy specimens were collected from each colonic segment. Endoscopic remission was defined as a Mayo endoscopic subscore with a grade of 0 or 1. Active histologic inflammation was defined by the presence of neutrophils infiltrating crypt epithelial cells. FC was determined by enzyme-linked immunosorbent assay analysis. Results Eighteen patients (30.5%) showed evidence of active histologic inflammation. Patients with active histologic inflammation had a significantly higher median level of FC (278 μg/g; interquartile range, 136–696 μg/g) than those without active histologic inflammation (68 μg/g; interquartile range, 30–172 μg/g) (P = .002). In multivariate analysis, the FC and Mayo endoscopic subscore (0 or 1) were each independent predictors of histologic inflammation. The level of FC identified active histologic inflammation in patients in clinical and endoscopic remission, with an area under the receiver operator characteristic curve value of 0.754. Conclusions Histologic inflammation is common among patients with UC in clinical and endoscopic remission. Patients with histologic features of inflammation can be identified reliably based on their fecal level of calprotectin.