SUMMARYLimited information is available on the incidence of Clostridium difficile infections (CDIs) in Italian hospitals. In this study, we assessed the changes in the incidence of CDI over a 5-year period in a teaching hospital in Liguria, the Italian region with the oldest population. Secondary endpoints were the development of severe CDI and 30-day mortality. The annual incidence of CDI/10000 patient-days significantly increased from 0·54 in 2010 to 3·04 in 2014 (χ² for trend, P < 0·001). The median age of patients with CDI was 81 years. As many as 81% and 89% of these patients had comorbid conditions and previous exposure to antibiotics, respectively. In the multivariate analysis of risk factors for severe CDI, previous therapy with histamine 2 blockers and low serum albumin were associated with severe CDI, while diabetes appeared to be protective. In the multivariate model of risk factors for 30-day mortality, high leukocyte count, low serum albumin, and increased serum creatinine were unfavourably associated with outcome. Strict adherence to infection control measures was of utmost importance to counteract the increasing incidence of CDI in our hospital, particularly because of the advanced age of the patients and their very high frequency of chronic conditions and use of antibiotics, which readily predispose them to the development of CDI.