Cultures of blood obtained from a patient with Staphylococcus epidermidis prosthetic valve endocarditis yielded 15 strains of S. epidermidis. Genome macrorestriction and amplified fragment-length polymorphism analyses of these strains showed that they belonged to 4 different, very closely related clones, suggesting that they were the result of genetic variability of an infecting strain during the infectious episode. In vivo experiments in a rat model for foreign body infections using 1 of the S. epidermidis strains from the patient showed genetic variability similar to that of the infecting strain. In the rat model, we also detected the simultaneous presence of different clones that were identical to those isolated from our patient, thus confirming the possibility of genetic variability. It is important to note that the 4 clones isolated from our patient presented with 2 different antibiograms. Therefore, in cases of foreign device-related infections due to coagulase-negative staphylococci, the possibility of polyclonal infection has to be taken into account, particularly as regards differences in antibiotic susceptibility.