Reports claiming that livestock, particularly pigs, could serve as a reservoir for the ‘superbug’ methicillin resistant Staphylococcus aureus (MRSA) shocked the medical and veterinary worlds when first discovered in Europe around 2004. Early studies identified a novel type of MRSA (ST398) in pigs in Europe, however the situation has become a bit more complicated since other varieties (e.g., ST9 in Asia and ST5 in North America, among others), have also been found in pigs. Unlike ST398 and ST9, which do not appear to contribute a significant role on human health in the USA, ST5 MRSA are among the most common type causing human clinical infections. Several studies have demonstrated a genetic basis for why ST9398 strains have a reduced ability to cause disease in humans. Until recently, similar studies had not been done on MRSA ST5 strains and so it remained unclear whether or not ST5 strains have the capacity to colonize and cause disease in humans. To address this question, this project obtained whole-genome sequences for 156 ST5 strains encompassing both MSSA and MRSA strains from both human and swine related sources. Additionally, this project tested the ability of these ST5 strains to adhere to skin cells obtained from humans. While working to finish the genome assemblies, we undertook a separate genetic comparison of our ST5 strains and found that the swine associated ST5 isolates uniformly lacked a set of genes known as the immune-evasion cluster (IEC) genes. These genes are central to the ability of S. aureus to cause serious infections in people, and are transmitted by a specific bacteriophage (virus infecting bacteria). This phage was also uniformly absent from the swine related isolates but present, along with IEC genes, in over 90% of the human ST5 isolates. The lack of IEC genes has been documented in ST398 MRSA and is thought to be related to the adaptation of the bacteria to animal hosts. Our conclusion from this study is that ST5 from swine related sources have a diminished capability to cause human disease compared with types circulating in the human population. Phylogenetic or family trees have been constructed using the core genome sequences from these ST5 strains. Additionally, in vitro binding assays were used to test the capacity of the ST5 strains to adhere to human keratinocytes. Combined the data from this study provide a comprehensive understanding of the origin, evolution, and zoonotic potential of LA-MRSA ST5 strains associated with swine to both the public health and veterinary communities.