Periprosthetic joint infection (PJI) causes significant morbidity. Methicillin sensitive Our hospital trust introduced MSSA screening and decolonisation prior to hip and knee arthroplasty in 2010. Data was prospectively collected since 2013, including all MSSA carriers, decolonisation treatment received, MSSA status at time of surgery and all PJIs. Prior to 2017 MSSA carriers received nasal mupirocin or neomycin, from August 2017 until August 2019 nasal octenidine was used. During the study period 15,958 primary hip and knee replacements were performed. 3,200 (20.1%) were MSSA positive at preoperative screening and received decolonisation treatment, 698 mupirocin, 1,210 neomycin and 1,221 octenidine. Mupirocin (89.1%) and neomycin (90.9%) were more effective at decolonisation than octenidine (50.0%, P<0.0001). There was no difference in S. aureus PJI rates (P=0.452). Of those negative at original screening 9.1% were positive on the day of surgery (1,164/12,758). MSSA decolonisation is an effective method to decrease PJI rates but there is little research into the best treatment. Both mupirocin and neomycin are more effective than octenidine at achieving MSSA decolonisation. There was poor correlation between the MSSA status after treatment and PJI rates. There is debate if treatment should be targeted by screening or if all patients she be treated without screening. Global decolonisation without screening is supported by the 26.7% of carriers that were negative at original screening in our study. Further research is needed comparing decolonisation treatments to reduce PJI rates and avoid the risk of drug resistance.