Staphylococcus aureus is a significant human pathogen that poses serious challenges to the healthcare system due to diverse immune-evasion strategies and its propensity for antibiotic resistance. Worldwide, it is the leading cause of skin and soft-tissue infections, osteomyelitis, septic arthritis, and infective endocarditis - originating from both community and healthcare-associated environments. Individually heterogeneous/diverse, S. aureus strains with a shared central genome are classified into Clonal Complexes (CC) based on the allelic variation of seven housekeeping genes. While the association between CC and immune evasion is not yet fully understood, the surface protein and virulence factor profiles uniquely associated with lineage may help predict pathogenic potential, gene carriage, and antibiotic resistance. We investigated key phenotypic and genetic variances in community associated S. aureus across three dominant lineages to distinguish CC-associated pathogenic determinants influencing distinct host-pathogen interactions to support the development of targeted treatment strategies. Previously, our lab generated two data sets using S. aureus clinical isolates: 1) Whole genome sequencing (WGS) of >120 isolates; 2) Tandem Mass Tag (TMT) Proteomic analysis of cell-wall lysates, containing staphylococcal surface proteins and bound serum proteins, extracted from 15 isolates representing CC5, CC8, CC30 (n≥4) following exposure to 10% human serum. The TMT abundance data was analyzed with QIAGEN Ingenuity Pathway Analysis (IPA) to reveal key differences and commonalities among S. aureus CCs across an array of biological pathways, molecular networks, and upstream regulatory processes based on interactions with human proteins. Comparative genomic analyses were performed using the WGS data. Galaxy and Geneious Prime were used to assemble consensus sequences and annotations across the 15 isolates to characterize the genomic variation among each CC. Annotations were used to generate a pan-genome to distinguish common and lineage-specific genotypic features, differences in gene presence, and sequence variations to develop a phylogenetic tree. IPA identified an immune-evasive phenotype in CC30 distinct from CC5 and CC8 in differential enrichment of pathways involving lipid metabolism, cellular transport, and immune signaling, while also validating the array of immunosuppressive features of USA300-dominant CC8. Furthermore, comparative-genomic analysis identified key variations in antibiotic gene carriage and a conserved core genome accompanied by considerable accessory genomic variation among the analyzed isolates, strongly distinguishing CC30 from CC5 and CC8. Together, these findings suggest that CC-associated phenotypic and genetic differences contribute to distinct host-pathogen interactions, including unique immune-evasive strategies, and may contribute to S. aureus success as a pathogen. Future studies will further characterize a subset of candidates involved in cell signaling and lipid metabolism to validate observed lineage-specific differences at the transcript level.