Background: The optimal duration of intravenous antibiotic therapy in Staphylococcus aureus prosthetic bone and joint infection has not been established. The objective of this study was to compare the effect of early and late intravenous-to-oral antibiotic switch on treatment failure. Patients and methods: We retrospectively analyzed all adult cases of S. aureus prosthetic bone and joint or orthopedic metalware-associated infection between January 2008 and December 2015 in a French university hospital. The primary outcome was treatment failure defined as the recurrence of S. aureus prosthetic bone and joint or orthopedic metalware-associated infection at any time during or after the first line of medical and surgical treatment within 2 years of follow-up. A Cox model was created to assess risk factors for treatment failure. Results: Among the 140 patients included, mean age was 60.4 years (SD 20.2), and 66% were male (n = 92). Most infections were due to methicillin-susceptible S. aureus (n = 113, 81%). The mean duration of intravenous antibiotic treatment was 4.1 days (SD 4.6). The majority of patients (119, 85%) had ≤5 days of intravenous therapy. Twelve patients (8.5%) experienced treatment failure. Methicillin-resistant S. aureus infections (HR 11.1; 95% CI 1.5-111.1; p = 0.02), obesity (BMI > 30 kg/m 2) (HR 6.9; 95% CI1.4-34.4, p = 0.02) and non-conventional empiric antibiotic therapy (HR 7.1; 95% CI 1.8-25.2; p = 0.005) were significantly associated with treatment failure, whereas duration of intravenous antibiotic therapy (≤ 5 or > 5 days) was not. Conclusion: There was a low treatment failure rate in patients with S. aureus prosthetic bone and joint or orthopedic metalware-associated infection with early oral switch from intravenous to oral antibiotic therapy.