Clostridium difficile infection (CDI) is a serious healthcare-associated infection and a growing health care problem, especially with the emergence of more virulent strains in the early 2000s. Clostridium difficile was first recognized as having the ability to cause pseudomembranous colitis in the late 1970s. CDI is now the most common cause of nosocomial infectious diarrhea. Asymptomatic colonization in healthy adults has been observed in only 3 percent of persons, while the prevalence of such colonization among residents in long-term-care facilities approaches 50 percent. Individuals colonized with Clostridium difficile serve as a reservoir for infection by contaminating the environment with Clostridium difficile spores, thus leading to the spread of the organism on the hands of health care workers or via use of medical equipment. CDI is increasing in incidence and, in all likelihood, severity. The number of cases diagnosed among patients discharged from hospitals increased from 31 per 100,000 persons in 1996 to 84 per 100,000 persons in 2005. Infection due to a relatively new strain of Clostridium difficile, termed "North American pulsed-field gel electrophoresis type 1" (NAP1), is felt to be at least partially responsible for this increased incidence of CDI as well as for the increased severity of clinical illness. The NAP1 strain is capable of producing more than 15 times the quantity of both toxins A and B, which are directly responsible for the damage to the intestinal tract of infected patients. Hence, CDI is not only now more common, but also more severe, leading to an attributable mortality of up to 16 percent of all deaths. A comparative effectiveness review (CER) was prepared by the Minnesota Evidence-based Practice Center (EPC) on Comparative Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection (December 2011). The purpose of the CER was to provide an overarching assessment of the evidence for comparing the accuracy of diagnostic tests and the effectiveness of prevention and treatment interventions on initial and recurrent CDI related patient outcomes in adults. Key informants, provided input to the EPC on the scope of the CER, agreed that its greatest contribution to the field could be to have an independent organization provide a comprehensive review of the major concerns of the field for both clinicians and researchers. The major impetus underlying the SR was a concern about the presence of clinical disease, not asymptomatic carriage of the Clostridium difficile organism.1 Molecular epidemiological studies whose main purpose was to identify the strains of Clostridium difficile present in the population were outside the scope of the CER. The CER focused on adult patients as they, particularly elderly adults, carry the most of the morbidity and mortality burden.The CER addressed the following Key Questions (KQs): 1. How do different methods for detection of toxigenic Clostridium difficile to assist with diagnosis of CDI compare in their sensitivity and specificity? a. Do the differences in performance measures vary with sample characteristics? 2. What are effective prevention strategies? a. What is the effectiveness of current prevention strategies? b. What are the harms associated with prevention strategies? c. How sustainable are prevention practices in health care (outpatient, hospital inpatient, extended care) and community settings? 3. What are the comparative effectiveness and harms of different antibiotic treatments? a. Does effectiveness vary by disease severity or strain? b. Does effectiveness vary by patient characteristics: age, gender, comorbidity, hospital versus community-acquired setting? c. How do prevention and treatment of CDI affect resistance of other pathogens? 4. What are the effectiveness and harms of nonstandard adjunctive interventions? a. In patients with relapse/recurrent CDI?