OBJECTIVES: To examine whether rapid PCR-based screening is a cost efficient tool to optimize pre-emptive antibiotic therapy of methicillin resistant and methicillin sensitive S. aureusinfections. METHODS: A decision analytic cost model was developed, based on data from peer-reviewed literature. Sensitivity analyses were undertaken to investigate the impact of variation in MRSA rate, cost ratio of the cost of appropriate antibiotic therapy to cost of inappropriate antibiotic therapy, PCR test cost and total hospital costs per case. RESULTS: At the current MSRA-rate of 24.5 % in Germany, PCR-guided treatment regimens are cost-efficient compared to empirical strategies. Costs of alternative treatment strategies differ, on average, up to € 1780 per case. A pre-emptive MSSA-treatment strategy with PCR test is least costly at lower rates of MRSA, while a pre-emptive MRSA-treatment strategy with PCR testing is the least costly approach when the MRSA rate is greater than 53.7%. An empirical MRSA-treatment strategy is least costly when the cost ratio is less than 1.06. When the total hospital cost per MRSA-case is increased, pre-emptive MSSA-treatment with PCR test achieves the lowest average cost, and the cost difference between the four treatment strategies increases. CONCLUSIONS: Early verification and adaptation of an initial pre-emptive antibiotic treatment of S. aureus infections using PCR-based tests are advantageous in most situations to be expected in Germany and other European countries. PCR tests accordingly should be considered as elements in antimicrobial stewardship programs.