Vancomycin was evaluated with and without gentamicin and/or rifampin in therapy for endocarditis due to methicillin-resistant Staphylococcus epidermidis in rabbits. Vancomycin (30 mg/kg iv every 12 hr), gentamicin (3.5 mg/kg im every 8 hr), rifampin (20 mg/kg im every 12 hr), combinations of vancomycin plus gentamicin, vancomycin plus rifampin, and vancomycin plus gentamicin plus rifampin were injected for two days, and the number of bacteria in vegetations was determined. Ratios of minimal inhibitory concentrations to minimal bactericidal concentrations (microgram/ml) for S. epidermidis were 3.1:25 for vancomycin, 0.2:0.8 for gentamicin, and 0.4:0.4 for rifampin. After two days of therapy, mean log colony-forming units +/- SD in vegetations were 7.1 +/- 1.5 (none of eight animals were sterile) for vancomycin; 4.6 +/- 2.2 (two of nine) for gentamicin; 4.5 +/- 2.2 (two of eight) for rifampin; 3.3 +/- 1.3 (three of 10) for vancomycin plus gentamicin; 2.7 +/- 1.2 (three of nine) for vancomycin plus rifampin; 2.1 +/- 0.2 (eight of nine) for vancomycin plus gentamicin plus rifampin; and 8.1 +/- 1.3 (none of 12) for the control group. Gentamicin, rifampin, vancomycin plus gentamicin, and vancomycin plus rifampin were significantly more effective than was vancomycin; vancomycin plus rifampin was more effective than was gentamicin alone; and the combination of vancomycin plus gentamicin plus rifampin was more effective than were the drugs administered alone or in the combinations vancomycin plus gentamicin and vancomycin plus rifampin. Two days of treatment followed by seven days of no treatment resulted in 71%, 29%, and 14% sterile vegetations in rabbits receiving the combination therapy vancomycin plus gentamicin plus rifampin, vancomycin plus rifampin, and vancomycin plus gentamicin, respectively.