Infective endocarditis is a severe disease with high mortality. Despite a global trend towards an increase in staphylococcal aetiologies, in older patients and a decrease in viridans streptococci, we have observed in recent studies great epidemiologic disparities between countries. In order to evaluate these differences among Mediterranean countries, we performed a PubMed search of infective endocarditis case series for each country. Data were available for 13 of the 18 Mediterranean countries. Despite great differences in diagnostic strategies, we could classify countries into three groups. In northern countries, patients are older (>50 years old), have a high rate of prosthetic valves or cardiac electronic implantable devices and the main causative agent is Staphylococcus aureus. In southern countries, patients are younger (<40 years old), rheumatic heart disease remains a major risk factor (45–93%), viridans streptococci are the main pathogens, zoonotic and arthropod-borne agents are frequent and blood culture–negative endocarditis remains highly prevalent. Eastern Mediterranean countries exhibit an intermediate situation: patients are 45 to 60 years old, the incidence of rheumatic heart disease ranges from 8% to 66%, viridans streptococci play a predominant role and zoonotic and arthropod-borne diseases, in particular brucellosis, are identified in up to 12% of cases.