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Identifying patients who are at high risk for severe Clostridium difficile–associated disease (CDAD) early in the course of their infection may help clinicians improve outcomes. Therefore, we compared clinical features associated with severe versus nonsevere CDAD by retrospectively reviewing records of hospitalized patients whose fecal assays were positive for C. difficile toxin. Of 336 patients, 12.2% had severe disease and 10.1% died from all causes. Regression modeling showed the following to be significantly associated with severe CDAD (p<0.05): age >70 years (odds ratio [OR] 3.35), maximum leukocyte count >20,000 cells/mL (OR 2.77), minimum albumin level <2.5 g/dL (OR 3.44), maximum creatinine level >2 mg/dL (OR 2.47), small bowel obstruction or ileus (OR 3.06), and computed tomography scan showing colorectal inflammation (OR 13.54). These clinical and laboratory markers for severe disease may be useful for identifying patients at risk for serious outcomes or death.