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Staphylococcus aureusis a major cause of severe infections including infective endocarditis, but lineage-specific virulence determinants remain unclear. We analyzed 77S. aureusbacteremic isolates from major lineages using phenotypic assays, infection models, and transcriptomics. Our results revealed significant heterogeneity inS. aureuspathogenicity. ST398 isolates exhibited heightened virulence, characterized by increased hemolysin production, whereas CC30 strains showed reduced growth, biofilm formation, and infectivity. Notably, the ST398agrCmutant Sau7 exhibited unique phenotypic behavior, with high biofilm production and decreased virulence inGalleria mellonellalarvae model. Infection studies in the rabbit experimental endocarditis model showed increased vegetation size and bacterial load in Sau7-infected animals, highlighting the role ofagrsystem inS. aureuscolonization and biofilm formation. Transcriptomic analysis identified key pathways, including quorum sensing systems and hemolysins, driving virulence in ST398 strains. These findings provide insights into the lineage-specific virulence mechanisms and the multifaceted nature ofS. aureuspathogenicity.