Methicillin-resistant Staphylococcus epidermidis is an important cause of cerebrospinal fluid shunt infections and prosthetic valve endocarditis. Agar dilution minimum inhibitory concentrations were determined for 100 strains of methicillin-resistant S. epidermidis which were isolated from clinical specimens. Vancomycin inhibited all 100 strains at ≤3.12 μg/ml, whereas clindamycin inhibited only 46 strains at ≤12.5 μg/ml. Methicillin-resistant S. epidermidis strains were resistant to achievable levels of erythromycin, with 90 strains having a minimum inhibitory concentration of ≥3.12 μg/ml. Of the five cephalosporins and one cephamycin tested, cefamandole was the most active in vitro, inhibiting 97 strains at ≤25 μg/ml. Antibiotic synergism was examined by a quantitative bacterial time-kill method. Synergism (≥102 kill by the combination over the most effective single antibiotic at 24 h) was demonstrated with vancomycin (1.56 μg/ml) plus cefamandole (6.25 μg/ml) in 14 of 14 strains, vancomycin plus cephalothin (6.25 μg/ml) in 14 of 14 strains, vancomycin plus rifampin (0.008 to 0.012 μg/ml) in 6 of 12 strains, rifampin plus cefamandole in 9 of 12 strains, and rifampin plus cephalothin in 10 of 12 strains. The emergence of populations of bacteria resistant to 0.2 μg of rifampin per ml developed in three of five methicillin-resistant S. epidermidis strains tested. The addition of either vancomycin, cephalothin, or cefamandole to the rifampin prevented the emergence of resistance in these three strains. Clinical trials of synergistic antibiotic combination therapy for serious methicillin-resistant S. epidermidis infections are indicated.