Staphylococcus aureus is a leading pathogen of implant-related infections. In the field of biomaterials a variety of alternative approaches are currently proposed for prophylaxis and treatment of implant infections, but little is known on the role of the different pathogenetic mechanisms and spreading strategies that lead selected S. aureus clones to prevail and become epidemic. This study aimed at identifying and characterizing the major clones in a collection of 200 S. aureus isolates from implant orthopaedic infections. Strain typing by automated ribotyping identified 98 distinct ribogroups. Ribogroups corresponded to specific accessory gene regulatory (agr) polymorphisms and possessed peculiar arrangements of toxins. The agr type II allele was more represented in epidemic clones, while agr type I in sporadic clones. A clear trend was observed, where epidemic clones resisted antibiotics more than sporadic ones. Conversely, the gene for lukD/lukE leukotoxin, found in 68% of the isolates, was unrelated to the level of clonal spreading. Surprisingly, the isolates of the most prevalent ribogroup were susceptible to almost all antibiotics and never possessed the lukD/lukE gene, thus suggesting the role of factors other than antibiotic resistance and the here investigated toxins in driving the major epidemic clone to the larger success.