Vancomycin-resistant Enterococcus faecium endocarditis is rare and usually occurs in immunocompromised patients. We describe a patient with hairy-cell leukemia and vancomycin-resistant E faecium endocarditis. The patient presented with severe aortic insufficiency. He underwent aortic root replacement with a cryopreserved aortic homograft and was treated with a combination of quinupristin/dalfopristin, ampicillin, and gentamicin.