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Sepsis remains a major cause of morbidity and mortality. Because of their frequent treatment with broad spectrum antibiotics, septic patients are at risk for developing secondary superinfections, such as Clostridium difficile infection (CDI). Recently both CDI and its case fatality rates have increased. We hypothesized that CDI is a frequent complication of and is associated with worse outcomes in sepsis. In 2004−2006 National Hospital Discharge Survey (NHDS) we identified all adult discharges carrying a sepsis ICD−9−CM diagnosis code. Within this cohort we identified discharges with a code for CDI. We used descriptive statistics to examine demographic, clinical and hospital characteristics and outcomes of these two groups. Crude mortality rates with and without CDI as a co−diagnosis served as the primary endpoint. Among 28,137 adults with sepsis 1,001 (3.6%) had a diagnosis of CDI. Those with CDI were older (73.2±14.9 vs. 66.9±17.6 years) and less likely to have multiple comorbidities. Specifically, diabetes (8.0% vs. 13.9%), chronic kidney disease (16.2% vs. 20.0%), and underlying immunologic (3.8% vs. 5.6%) and hematologic (3.8% vs. 5.4%) disorders were noted more commonly among septic patients not developing CDI. However, crude hospital mortality was higher among CDI+ than CDI− septic discharges (OR 1.36, 95% CI 1.16−1.58). Similarly, CDI was associated with an increased hospital LOS (14.3±13.8 vs. 10.9±12.9 days, p<0.0001) and a decreased rate of routine home discharge (20.5% vs. 39.2%, p<0.0001). Adults with sepsis face a significant risk for CDI. Despite the observation that those developing CDI have fewer chronic illnesses, CDI was associated with >1/3 increase in crude morality rate in sepsis. Preventive measures are urgently needed in this population and clinicians must remain vigilant to this complication in sepsis. This abstract is funded by: None. Am J Respir Crit Care Med 179;2009:A5490 Internet address: www.atsjournals.org Online Abstracts Issue