OBJECTIVE To evaluate the efficacy of oral linezolid, with or without rifampicin, on valve vegetations and secondary foci of infection compared with vancomycin, in the absence or presence of rifampicin, in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. METHODS Treatment groups were controls (n = 16), linezolid (n = 15), vancomycin (n = 15), linezolid and rifampicin (n = 15), vancomycin and rifampicin (n = 13), linezolid relapse (n = 11) and vancomycin relapse (n = 9). Therapy lasted 5 days in all groups, with survival of animals in the linezolid relapse and vancomycin relapse groups being recorded for an additional 5 days. Blood was drawn to determine the linezolid concentration, and valve vegetations, and kidney, liver, lung and spleen segments were collected for culture. RESULTS Survival in each individual group was higher than that in the control group; bacterial load in valve vegetations was reduced by all treatment regimens, with linezolid exhibiting bactericidal effects. Bactericidal activity of linezolid was noted in all secondary foci of infection except the lung, where only the combination of rifampicin with linezolid was bactericidal. CONCLUSIONS Orally administered linezolid is effective in limiting bacterial growth in the secondary foci of endocarditis. Co-administration of rifampicin favoured the suppression of bacterial growth in the lung.