OBJECTIVE To examine biopsy specimens for histologic features suggestive of Clostridium difficile infection in patients with ulcerative colitis (UC). METHODS Nine patients with UC had colonic biopsy specimens taken during a symptomatic flare that coincided with positive C difficile (C difficile+) tests. Twenty-eight controls were biopsied during a UC flare but tested negative for C difficile. We reviewed the slides for evidence of pseudomembranes, ischemic-like changes, degree of colitis, and lamina propria hemorrhage. RESULTS In C difficile+ patients, 4 (44.4%) of 9 had microscopic pseudomembranes compared with 11% in controls (P < .05). Other histologic/clinical features were not predictive. CONCLUSIONS Although the presence of microscopic pseudomembranes suggests C difficile infection in patients with UC, sensitivity and specificity are poor; biopsy findings do not reliably detect this infection in patients with UC.