Staphylococcus epidermidis is a major pathogen in early prosthetic valve endocarditis and cerebrospinal fluid shunt infections. Approximately 10 to 15% of hospital isolates are methicillin resistant. Ten clinically significant isolates of the latter were collected for antibiotic studies in vitro and in an experimental infection in animals. Time-kill studies of five strains showed gentamicin to be the single most effective antibiotic; however, dwarf colony variants emerged as survivors with two of these strains when challenged with gentamicin alone. The addition of a second antibiotic to gentamicin did not significantly improve the bactericidal rate but prevented the emergence of variant strains. A blood culture isolate of methicillin-resistant S. epidermidis combined with 5% hog gastric mucin was used to establish an experimental intraperitoneal infection in mice. Neither methicillin nor nafcillin treatment reduced mortality below that of untreated animals. Cephalothin treatment delayed early mortality but did not diminish overall mortality. Gentamicin was the most effective single antibiotic, and gentamicin in combination with vancomycin was the most effective regimen overall. The combination of rifampin plus vancomycin was as effective as gentamicin alone. The combinations of cephalothin or nafcillin with gentamicin and cephalothin with vancomycin demonstrated antagonism. The antagonism was not due to multiple injections or drug-drug inactivation.