BACKGROUND: Recurrent or persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia presents significant clinical challenges. Comprehensive genomic-scale studies on the genetic changes in MRSA that correspond to refractory bacteremia are lacking. METHOD: From 2011 to 2019, MRSA blood isolates were collected from patients with persistent or recurrent bacteremia at a teaching hospital in southern Taiwan. Whole-genome sequencing (WGS) captured the genomic changes in strains responsible for refractory bacteremia, and the altered susceptibilities to specific antimicrobial agents were assessed through measurements of minimal inhibitory concentrations (MICs). RESULT: A total of 35 MRSA blood isolates from 15 patients with recurrent or persistent bacteremia were analyzed. Reduced susceptibilities to at least one anti-MRSA agent developed in strains from seven (46.7 %) patients. Of them, a non-synonymous mutation on a global regulator mgrA was associated with reduced daptomycin susceptibility, while an increase in vancomycin MIC was linked to mutations in genes encoding LCP family protein. A 16-fold increase in MIC to fusidic acid was connected to a mutation in the elongation factor G. These recurrent strains commonly exhibited a loss or acquisition of adhesion genes that were involved in biofilm formation, including fnbA, fnbB, and sdrD, and easG series genes of type VII secretion system. CONCLUSION: Changes in the susceptibility of successive strains to common anti-MRSA agents were frequently observed in recurrent MRSA bacteremia. These changes were linked to modifications in genes of regulatory cascade, peptidoglycan binding, adhesion, and type VII secretion system.