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Studies have demonstrated an increasing Clostridium difficile infection (CDI) incidence in hospitals and the community, with increasing morbidity and mortality. In this study, we analyzed data from the National Hospital Discharge Survey (NHDS) to evaluate CDI epidemiology, outcomes, and predictors of mortality in hospitalized adults. We identified cases of CDI (and associated comorbid conditions) from NHDS data from 2005 through 2009 using ICD-9 codes. Weighted univariate and multivariate analyses were performed to ascertain CDI incidence, associations between CDI and outcomes [length of stay (LOS), colectomy, all-cause in-hospital mortality, and discharge to a care facility], and predictors of all-cause in-hospital mortality. Of an estimated 162 million adult inpatients, 1.26 million (0.8 %) had CDI. The overall CDI incidence is 77.8/10,000 hospitalizations, with no statistically significant change over the study period. On multivariate analysis, after adjusting for age, gender, and comorbid conditions, CDI is an independent predictor of longer LOS (mean difference, 2.35 days), all-cause mortality [odds ratio (OR) 1.45], colectomy (OR 1.41), and discharge to a care facility (OR 2.12) (all P < 0.001). Elderly patients have a higher CDI incidence and worse outcomes than younger adults. The strongest predictors of all-cause mortality in patients with CDI include age 65 years or older, colectomy, and coagulation abnormalities. Despite stable CDI incidence and advances in management, CDI is associated with increased LOS, colectomy, all-cause in-hospital mortality, and discharge to a care facility in hospitalized, especially elderly, adults. Age older than 65 years should be added to the severity criteria for CDI. [ABSTRACT FROM AUTHOR]