Twenty-three patients with prosthetic valve endocarditis caused by methicillin-resistant Staphylococcus epidermidis were studied retrospectively for assessment of the role of rifampin treatment. Rifampin (900-1,200 mg daily) was administered in combination with either vancomycin or a β-Iactam antibiotic for an average of 38 days. Eight patients also received an aminoglycoside. Infection was cured in 16 (70%) of these patients; i.e., in 13 (87%) of 15 receiving rifampin plus vancomycin and in three (38%) of eight receiving rifampin plus a fJ-Iactam antibiotic (P =.025). The addition of rifampin to vancomycin regimens resulted in an increase in serum bactericidal activity. The selection of rifampin-resistant strains of S. epidermidis during treatment with a combination of antibiotics was noted in two patients with persistent infection. The rates of cure obtained with rifampin-β-lactam combinations were similar to those obtained with β-lactam agents alone however, the cure rates obtained with rifampin plus vancomycin (with or without an aminoglycoside) were encouraging and merit further study. © 1983 by The University of Chicago. All right reserved.