BACKGROUND The incidence of Clostridium difficile infection is increasing in the United States. The aim of our investigation is to compare short-term and long-term outcomes of patients admitted with an ulcerative colitis (UC) flare and co-existent C. difficile infection to those of non-infected patients. METHODS A historical cohort study was undertaken examining admissions at Mount Sinai Hospital between June 2004 and June 2005 using ICD-9 criteria for UC. Charts were abstracted for those patients for whom C. difficile testing was performed. RESULTS Of 288 admissions, 99 charts met the inclusion criteria. Fifty-two patients were C. difficile-negative and 47 were positive. Demographic data and laboratory values upon admission did not differ between the two groups. Patients who were C. difficile-positive had significantly more UC-related hospitalizations and emergency room visits in the year following initial admission (58 visits vs. 27, P = 0.001 and eight visits vs. 1 visit (P = 0.012), respectively). One year following the index admission, C. difficile patients had significantly higher rates of colectomy compared to C. difficile-negative patients (44.6% vs. 25%, P = 0.04). Length of hospitalization (11.7 vs. 11 days), use of cyclosporine therapy during index admission (48% vs. 47% of patients), and percentage requiring colectomy at initial admission (23.4% vs. 13.5%) did not reach statistical significance. CONCLUSIONS Our data suggest that patients presenting with a UC flare who are infected with C. difficile have worse long-term clinical outcomes than those that are C. difficile-negative. C. difficile testing should be performed for all patients presenting with UC flare. Further studies are warranted to elucidate how infection can alter the natural history of UC.