The endogenous or exogenous origin of Staphylococcus aureus, responsible for orthopaedic surgical-site infections (SSI), remains debated. We conducted a multicentre prospective cohort study to analyse the respective part of exogenous contamination and endogenous self-inoculation by S. aureus during elective orthopaedic surgery. The nose of each consecutive patient was sampled before surgery. Strains of S. aureus isolated from the nose and the wound, in the case of SSI, were compared by antibiotypes or pulsed-field gel electrophoresis (PFGE). A total of 3,908 consecutive patients undergoing orthopaedic surgery were included. Seventy-seven patients developed an SSI (2%), including 22 related to S. aureus (0.6%). S. aureus was isolated from the nose of 790 patients (20.2%) at the time of surgery. In the multivariate analysis, S. aureus nasal carriage was found to be a risk factor for S. aureus SSI in orthopaedic surgery. However, only nine subjects exhibiting S. aureus SSI had been found to be carriers before surgery: when compared, three pairs of strains were considered to be different and six similar. In most cases of S. aureus SSI, either an endogenous origin could not be demonstrated or pre-operative nasal colonisation retrieved a strain that was different from the one recovered from the surgical site.