Clostridium difficile infection (CDI) is a potentially serious disease for which the epidemiology has recently changed, because of an emerging drug-resistant strain of the pathogen. Metronidazole and oral vancomycin are the primary treatment agents.2 Metronidazole has been historically favored as the first-line agent, partly to reduce the selection pressure for vancomycin-resistant enterococci (VRE), although metronidazole can also select for VRE. Vancomycin was traditionally reserved for metronidazole treatment failure or life-threatening disease. In a study conducted before emergence of the epidemic strain, vancomycin was reported to be superior for the initial treatment of severe CDI and for treatment of CDI that does not respond to metronidazole. Expert opinion calling for the use of vancomycin as first-line therapy, especially for severe CDI emergence of the epidemic strain, and reports of decreased metronidazole efficacy may have impacted CDI treatment practices. The purpose of this study was to characterize trends in CDI treatment in US hospitals.