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Entering host cells, bacteria hide from host immune defenses, shelter from extracellular antibiotics, and cause chronic infection. <jats:italic>Staphylococcus aureus<\/jats:italic>, the leading etiologic agent of orthopedic implant infections, is able to enter bone cells and induce osteoblast apoptosis, osteoclast recruitment, and highly destructive osteomyelitis. <jats:italic>Staphylococcus epidermidis<\/jats:italic>, <jats:italic>Staphylococcus lugdunensis<\/jats:italic>, and <jats:italic>Enterococcus faecalis<\/jats:italic> are opportunistic pathogens causative of implant\u2010related infections. This study investigated the ability to internalize into osteoblastic MG63 cells of 22 <jats:italic>S. epidermidis<\/jats:italic>, 9 <jats:italic>S. lugdunensis<\/jats:italic>, and 21 <jats:italic>E. faecalis<\/jats:italic> clinical isolates from orthopedic implant infections. Isolates were categorized in clusters by ribotyping. Internalization assay was carried out by means of a microtiter plate\u2010based method. <jats:italic>S. epidermidis<\/jats:italic>, <jats:italic>S. lugdunensis<\/jats:italic>, and <jats:italic>E. faecalis<\/jats:italic> strains turned out incompetent to enter osteoblasts, exhibiting negligible internalization into MG63 cells, nearly three orders of magnitude lower than that of <jats:italic>S. aureus<\/jats:italic>. Osteoblast invasion does not appear as a pathogenetic mechanism utilized by <jats:italic>S. epidermidis<\/jats:italic>, <jats:italic>S. lugdunensis<\/jats:italic>, or <jats:italic>E. faecalis<\/jats:italic> for infecting orthopedic implants. Moreover, it can be inferred that intracellularly active antimicrobials should not be necessary against implant infections caused by the three bacterial species. Finally, implications with the uptake of biomaterial microparticles by nonphagocytic cells are enlightened. \u00a9 2015 Wiley Periodicals, Inc. 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