The effectiveness of ciprofloxacin and/or novobiocin therapy was assessed for experimental endocarditis caused by three strains of Enterococcus faecium resistant to ampicillin, vancomycin, and aminoglycosides. Rabbits with endocarditis caused by two of the strains had a significant decrease in bacterial counts in vegetations when treated with both antibiotics. Further studies using combination therapy with ciprofloxacin plus novobiocin for multidrug resistant strains of E. faecium are warranted.