OBJECTIVES Methicillin-resistant Staphylococcus aureus (MRSA) infections cause heavy financial burden on healthcare systems worldwide. Hospital admission screening has been proven as an effective method to prevent nosocomial MRSA transmission. However, previous cost studies mostly refer to screening regimes for a limited area of hospitals (e.g. ICU) a limited period of intervention (< 1 year) or rely on culture tests only. The aim of this study was to determine the long-term costs and benefits of a targeted hospital wide PCR-based admission screening for MRSA. METHODS We performed a six-year (2008-2013) retrospective analysis of the step-wise implementation of a hospital-wide PCR-based admission screening of defined risk patients for MRSA in a 926-bed tertiary hospital. Screening costs includes PCR-screening (screening rate 10.7-14.7%) and cultural test confirmation in case of a positive test result as well as hygienic measures for pre-emptive isolation of all screened patients. The benefit is calculated based on prevented nosocomial MRSA infections (reference year 2007), assuming that 8,673 Euros will be saved per case. RESULTS During the study period, prevented nosocomial MRSA-infections resulted in total cost savings of at least 1,329,714 Euros. This is opposed by costs for targeted PCR-screening of 670,234 Euros and 441,448 Euros for pre-emptive isolation measures. The save/cost-ratio was calculated with 1.196, the save-cost-difference with 36,339 Euros per year. CONCLUSIONS Our study shows the advantage of a PCR-based admission screening by a positive cost-saving-difference. Nevertheless, this advantage depends on cost drivers included in the analysis and the definition of risk factors which determine the proportion of patients to be screened. For a true image, the opportunity costs for reimbursement losses due to blocked beds during isolation as well as additional savings for prevented nosocomial MRSA-colonizations have to be taken into consideration.