e Clostridium difficile infection (CDI) became a public health problem for the global spreading of the so-called hypervirulent PCR ribotypes (RTs) 027 and 078, associated with increases in the transmission and severity of the disease. However, especially in Europe, several RTs are prevalent, and the concept of hypervirulence is currently debated. We investigated the toxin and resistance profiles and the genetic relatedness of 312 C. difficile strains isolated in a large Italian teaching hospital during a 5-year period. We evaluated the role of CDI-related antibiotic consumption and infection control practices on the RT predominance in association with their molecular features and transmission capacity. Excluding secondary cases due to nosocomial transmission, RT018 was the predominant genotype (42.4%) followed by RT078 (13.6%), while RT027 accounted for 0.8% of the strains. RT078 was most frequently isolated from patients in intensive care units. Its prevalence significantly increased over time, but its transmission capacity was very low. In contrast, RT018 was highly transmissible and accounted for 95.7% of the secondary cases. Patients with the RT018 genotype were significantly older than those with RT078 and other RTs, indicating an association between epidemic RT and age. We provide here the first epidemiological evidence to consider RT018 as a successful epidemic genotype that deserves more attention in clinical practice.C lostridium difficile infection (CDI) is one of the most common hospital-acquired infections and the main known cause of antibiotic-associated diarrhea in hospitals in industrialized countries (1). Previous antibiotic treatment, hospitalization, old age, and underlying diseases represent major risk factors for CDI. The disease spectrum ranges from mild diarrhea to severe pseudomembranous enterocolitis, sepsis, and death (2, 3).In the past decade, many countries in North America and Europe have registered an increase in CDI rates and related severity and mortality (4, 5). These epidemiological changes coincided with the emergence and epidemic spread of C. difficile strains belonging to the PCR ribotype (RT) 027/North American pulsedfield gel electrophoresis type 1 (NAP1) (6). Indeed, RT027 became the predominant strain in many geographical regions, as documented in different epidemiological studies, and, since 2005, several countries have conducted epidemiological surveillance to monitor its spread (7,8). It has been reported to occur in at least 38 U.S. states and in 16 European countries, being also responsible for outbreaks (7, 9). Moreover, an increase in community-acquired CDI has been reported; in Europe, this phenomenon correlates with the diffusion of RT078/NAP7 or NAP8 which, like RT027, has been associated with higher disease severity and attributable mortality (1, 10).RT027 and RT078 are often referred to as hypervirulent genotypes of C. difficile, but this definition is not without controversy. Though this term denotes an increase in virulence, it has often been misused to ident...