Endocarditis due to multidrug-resistant Enterococci and specifically multidrug-resistant Enterococcus faecium (E. fαecium) is rare. Optimal antimicrobial therapy still remains undefined and a challeging issue. We report a case of native valve endocarditis due to vancomycin-resistant E. faecium (VRE) in a 65-years-old man with significant comorbid conditions.