BACKGROUND: This study aimed to provide a contemporary picture of the epidemiologic, clinical, microbiologic characteristics and in-hospital outcome of infective endocarditis (IE) observed in a single center in Italy. METHODS: We performed a retrospective study of patients with definite or probable IE observed at the "L. Sacco" Hospital in Milan, Italy, from January 1, 2003 through December 31, 2010. RESULTS: 189 episodes of IE in 166 patients were included. The mean number of incident IE in the study period was of 1.27 (range 0.59-1.76) cases per 1000 patients admitted. The median age of the cohort was 57 (interquartile range, 43-72) years, 63% were male and 62.5% had native valve IE. Twenty-six percent were active intravenous drug users (IVDU), 29% had a health care-associated IE and 5% chronic rheumatic disease. Twenty-nine percent of the cases occurred in patients affected by chronic liver disease and 19% in HIV positive subjects. Staphylococcus aureus was the most common pathogen (30%), followed by streptococci. The mitral (34%) and aortic (31%) valves were involved most frequently. The following complications were common: stroke (19%), non-stroke embolizations (25%), heart failure (26%) and intracardiac abscess (9%). Surgical treatment was frequently employed (52%) but in hospital mortality remained high (17%). Health care-associated IE and complications were independently associated with an increased risk of in-hospital death, while surgery was associated with decreased mortality. CONCLUSION: S. aureus emerged as the leading causative organism of IE in a University hospital in northern Italy. Our study confirmed the high in-hospital mortality of IE, particularly if health care associated, and the protective role of surgery.