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A total of 271 patients were prospectively followed up to determine whether patients whose hospital stay is complicated by diarrhea due to Clostridium difficile experience differences in cost and length of stay and survival rates when compared with patients whose stay is not complicated by C. difficile–associated diarrhea. Forty patients (15%) developed nosocomial C. difficile–associated diarrhea. These patients incurred adjusted hospital costs of $3669—that is, 54% (95% confidence interval [CI], 17%–103%)—higher than patients whose course was not complicated by C. difficile–associated diarrhea. The extra length of stay attributable to C. difficile–associated diarrhea was 3.6 days (95% CI, 1.5–6.2). C. difficile–associated diarrhea was not associated with excess 3-month or 1-year mortality after adjustment for age, comorbidity, and disease severity. On the basis of the findings of this study, a conservative estimate of the cost of this disease in the United States exceeds $1.1 billion per year.