Clostridium difficile accounts for 15-25% of cases of antibiotic-associated diarrhea (AAD) and for virtually all cases of antibiotic-associated pseudo-membranous colitis (PMC). This anaerobic bacterium is also carried in the gastro-intestinal tract of less than 3% of the normal adult population and can be isolated from the feces of 50-70% asymptomatic neonates. Since recent years, C. difficile has been identified as the leading cause of nosocomial diarrhea in adults. Pathogenesis relies on a disruption of the normal bacteria flora of the colon, a colonization with C. difficile and the release of toxins that cause mucosal damage and inflammation. Incidence of C. difficile intestinal disorders varies between 1 to 30 per thousand patient admissions. Risk factors for C. difficile-associated diarrhea include antimicrobial therapy, older age (> 65 years), intensive care, nasogastric tube, anti-acid use, and length of hospital stay. Nosocomial transmission of C. difficile via orofecal route occurs in 3-30% of total patient admissions but it often remains asymptomatic. Environmental contamination and carriage of the organism on the hands of hospital staff are common. Measures that are recommended to reduce cross-infection rely on an accurate and rapid diagnosis, implementation of enteric isolation, use of disposable gloves, hand washing with a suitable disinfectant (e.g. chlorhexidine) and daily environmental disinfection. C. difficile is a common cause of infectious diarrhea and should be therefore systematically investigated in patients with nosocomial diarrhea.