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Even in the modern era of advanced diagnostic imaging, improved antibiotic therapy and potentially curative surgery, infective endocarditis remains a serious disease with high rates of morbidity and mortality. Reasons for such a persistently poor outcome may be represented by the changing epidemiology and microbiology, with new groups of patients at risk and new and more aggressive microorganisms. However, the inadequate use of both diagnostic (blood cultures and echocardiography) and therapeutic (antibiotics and surgery) means can influence the generally delayed diagnosis and poor prognosis seen in patients with infective endocarditis. We tried to identify the critical points in the management of patients with infective endocarditis and to elaborate a formal multidisciplinary approach based on the strict collaboration of specialists in infectious diseases, microbiology, cardiology and cardiac surgery. We hypothesized that this approach could increase the adherence to the published guidelines, and could represent a means to improve the outcome of patients with infective endocarditis.