We have examined whether topical perioperative prophylaxis can reduce the incidence of methicillin-resistant Staphylococcus aureus (MRSA) surgical site infections (SSIs). Using a controlled before and after approach on patients from four orthopaedic wards, undergoing orthopaedic surgery involving insertion of metal prostheses and/or fixation, received perioperative prophylaxis with nasal mupirocin for five days, and a shower or bath with 2% (v/v) triclosan before surgery (PPNMT). After introduction of PPNMT there was a marked decrease in incidence of MRSA SSIs (per 1000 operations) from 23 in the six months beforehand (period A) to 3.3 (P<0.001) and 4 (P<0.001) in subsequent consecutive six-month periods (B and C, respectively). Of 11 MRSA SSI cases that occurred during periods B and C, only one had actually received PPNMT, and 10 occurred after acute, as opposed to elective, surgery (P<0.001). Point prevalence nasal MRSA carriage decreased from 38% before PPNMT to 23% immediately after, and 20%, 7%, 10% and 8% (P<0.001) at six-monthly intervals post-intervention. Conversely, the prevalence of nasal MRSA carriage in a control elderly medicine ward did not change significantly. Vancomycin usage, in terms of defined daily doses, declined by 23%. Low-level mupirocin resistance was found in 2.3% of S. aureus isolates from orthopaedic patients before PPNMT, and in 3.9%, 6.1%, 10% and 0% in subsequent six month periods. No S. aureus isolates with high-level mupirocin resistance were found. PPNMT can reduce the incidence of MRSA SSls after orthopaedic surgery, probably by reducing nasal MRSA carriage in the endemic setting, without selecting for mupirocin resistance.