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With improved survival in burn patients, Clostridium difficile infection (CDI) remains a significant potential complication. The incidence of, risk factors for, and outcomes of CDI in severely burned patients are poorly studied and remain unclear. This study involves retrospective case control and cohort studies using electronic medical records from February 1, 2002 to January 31, 2009 at the US Department of Defense’s only burn unit. Demographic, risk factor, and outcome data were collected for all C. difficile toxin positive patients in the burn, medical, and surgical intensive care units and the hospital’s step down unit along with an additional analysis of a 2:1 matched control of C. difficile toxin negative to positive burn patients. In the burn intensive care unit (BICU) population there was an incidence of 7.9 cases per 10,000 patient days; less than the non-burn unit rate of 15.2 cases (p-value < 0.01). The BICU patients were young males with a median 42% total body surface area burns. There were higher frequencies of operations and prior aminoglycoside use, with longer unit stays and times until death or discharge. There was no difference in treatments, morbidity, or mortality. The comparison of patients with positive and negative C. difficile toxin among those in the BICU revealed few significant differences in risk factors or outcomes. Differences in risk factors between burn and non-burn patients were likely markers of the populations rather than independent risk factors for CDI in the burn population with overall lower rates likely reflective of younger, healthier patients in the BICU and more aggressive infection control practices.