The goal of this thesis was to advance understanding of the epidemiology of Staphylococcus aureus in the US swine industry, particularly in relation to potential human health risks from this animal reservoir. The studies were conducted to investigate the prevalence of S.aureus in swine and swine veterinarians in the USA. A total of 720 nasal swabs (20 swabs per herd) were collected from 36 herds and self-nasal samples from 66 swine veterinarians were submitted every month for 18 months. The patterns of S.aureus colonization were determined based on molecular epidemiological methods (MLST and spa typing). Antimicrobial susceptibility testing, enterotoxin genes, immune evasion cluster genes testing were performed to identify their characterizations. Later, a subset of 76 isolates purposely selected was submitted for whole genome sequencing analysis. In swine study, MRSA was not detected in any of the 35 herds except a positive control herd. S.aureus was detected from 76% of pigs sampled. In case of swine veterinarians, the prevalence of S.aureus (avg 65%, monthly range from 58-82%) and MRSA (avg 9%, monthly range from 6-15%) were confirmed suggesting elevated risk of nasal colonization. Similar distribution of genotypes between swine and swine veterinarians were observed. The patterns of phenotypic antibiotic resistance, the absence of enterotoxin genes and IEC genes also showed relatively similar regardless of host species. In addition, WGS data supported that there were unique traits of putative virulence genes and antibiotic resistance genes by each genotype. All the data generated in this dissertation provide a comprehensive assessment of swine associated S.aureus giving a crucial insight into the phenomenon of interspecies dissemination.