Ampicillin or amoxicillin at 625-800 mg/kg/day, in combination with a β-Iactamase inhibitor, each is as effective as vancomycin in animal models of methicillin-resistant Staphylococcus aureus endocarditis. Studies were done to determine whether the addition of rifampin would permit lowering the dose of ampicillin into the range recommended for use in humans without loss ofefficacy. The efficacy ofarnpicillin/sulbactam (300/150 or 150/75 mg/kg/day intramuscularly, in three divided doses) in combination with rifampin (5 mg/kg intramuscularly, three times daily) was compared with that of vancomycin (25 mg/kg intravenously, twice daily, or 30 mg/kg intramuscularly, three times daily) in the rabbit model of methicillin-resistant S. aureus aortic valve endocarditis. Neither ampicillin/sulbactam nor rifampin alone was effective. The ampicilIin/sulbactam/rifampin regimen was as effective as vancomycin. This regimen may be an alternative to vancomycin in treatment of methicillin-resistant S. aureus infections.