Background Knowledge of the antibiotic susceptibility profiles of the bacteria responsible for osteoarticular infections is crucial for choosing the appropriate empirical antibiotic regimen. Wide use of broad spectrum antibiotics in these infections may have lead to selection of resistant bacteria. The aim of our study was to answer to these questions: (1) Did the bacterial pathogens isolated from osteoarticular infections (OAIs) and their antibiotic susceptibility profile change over the 10-year period in our University Hospital, particularly for Staphylococcus aureus and Coagulase negative staphylococci? (2) Are the antibiotics used for post-operative antibiotic therapy still effective against staphylococci involved in OAIs? (3) Are the antibiotics used for documented therapy still effective against staphylococci involved in OAIs? Hypothesis We hypothetise that bacterial epidemiology and antibiotic resistance rates have changed little thanks to a reasoned prescription of antibiotics in our Center. Materials and methods We performed a retrospective study describing the antibiotic susceptibility profile of bacteria isolated from osteoarticular infections over 10 years in our University Hospital, with a focus on the Staphylococcus genus. Results A total of 3474 staphylococci were included (2373 coagulase negative staphylococci and 1101 S. aureus), 34.8% (1207/3469) of which were resistant to methicillin. Antibiotic susceptibility profiles remained quite stable between 2010 and 2019, except for rifampicin (14.1% (45/318) versus 5.7% (23/401), p = 0.0001) and fluoroquinolones (35.3% (109/309) versus 20.3% (81/399), p = 0.000008) for which resistance rates significantly decreased even among methicillin-resistant strains. Discussion In spite of wide use of antibiotics in orthopaedic units, overall resistance rates did not increase over the last 10 years. The prescription of these molecules in combination regimens guided by the antibiotic susceptibility patterns performed on reliable samples and on the basis of multidisciplinary discussions may explain these results. Level of evidence IV, retrospective study.