Endocarditis was produced in rabbits with a methicillin-resistant Staphylococcus epidermidis isolate. Subpopulations resistant to other semisynthetic penicillins and cephalosporins were detected in the isolate. Their presence was probably responsible for the increase in minimum bactericidal concentrations and minimum inhibitory concentrations when tests with high inocula, rather than low inocula were pursued. Rabbits were treated for either 2 or 7 days with nafcillin, cephalothin, cefamandole, vancomycin, rifampin, or gentamicin. Spontaneous death was uncommon in either controls (84% survival) or treated animals (80 to 94% survival). There was no significant difference in the number of bacteria in vegetations of rabbits treated for 7 days with cephalothin, cefamandole, nafcillin, or no antibiotic (control). There was a significant reduction in total bacteria in vegetations of rabbits given vancomycin, gentamicin, or rifampin for 7 days as compared with cephalothin, cefamandole, nafcillin or control. Gentamicin or rifampin sterilized significantly more vegetations after 7 days than cephalothin, cefamandole, nafcillin, or control; rifampin was more effective in sterilizing vegetations than either gentamycin or vancomycin after 2 days. Mutants resistant to 10 mug of rifampin per ml comprised the total bacterial population cultured from vegetations of 2 of 17 rabbits treated with this antibiotic for 7 days; there was no change in the susceptibility of vegetation isolates to other antibiotics. Rifampin, vancomycin, or gentamicin may prove to be more effective in humans than cephalosporins or semisynthetic penicillins in the treatment of methicillin-resistant S. epidermidis endocarditis.