Rationale, aims and objectives Surgical-site infections (SSI) are associated with increases in hospital length of stay and hospitalization costs and patient’s poor quality of life. Eradication of S. aureus with nasal mupirocin could decrease the incidence of SSI by this pathogen. The primary purpose of our study was to evaluate the incidence of SSI before and after the implementation of a decolonisation program in orthopaedic patients. Methods A pre-post intervention study was conducted. A multidisciplinary group elaborated and implemented a standard procedure for nasal decolonisation, including a pharmacy visit. The proportion of patients who had a SSI and those infected by S. aureus were the primary outcome variables. The proportion of pre-screened patients, nasal carriers, and adequate prophylaxis (3 mupirocin applications) and decolonisation (5 applications) were recorded to analyse program implementation. Mupirocin resistance or adverse effect were also registered. Results 1,192 patients were included in the study (599 pre- and 593 post-intervention group) SSI were recorded in 2.5% vs 2.0% of patients (pre vs post-intervention), showing a relative risk (RR) of 0.81 (p=0.58). S. aureus infections were recorded in 0.7% vs 0.3% (p=0.420, RR=0.51). 59.2% vs 3.5% of patients were pre-screened (p<0.001). 63 patients (17.9%) were nasal carriers of S. aureus, of which 58 (92.1%) received an adequate prophylaxis and 32 (50.8%) an adequate decolonisation. No infection was reported regarding patients who received adequate nasal prophylaxis. Conclusions The nasal prophylaxis and decolonisation protocol were implemented in the orthopaedic patient flow. Eradication of S. aureus with nasal mupirocin seem to decrease the incidence of S. aureus infections.