show Abstracthide AbstractStaphylococcus aureus bacteremia (SAB) is a serious medical condition and may be fatal if inadequately treated. A major concern is the emergence and spread of drug resistant S. aureus in bloodstream infections, which is associated with therapeutic failure and increased mortality. We hypothesized that the blood is a unique ecological niche that selects for a distinct set of genomic variants, favoring the successful adaptation and persistence of certain lineages in the larger population over the long term. We generated high quality draft genomes from 323 SAB isolates from the Dartmouth-Hitchcock Medical Center, New Hampshire, USA sampled in 2010 - 2018. Results showed a phylogenetically diverse SAB population dominated by two methicillin-resistant lineages. The lineage consisting of clonal complex 8 emerged in the mid-1940s and its population has steadily increased until the late 1960s when it started to level off. This plateau coincided with the rapid increase of a second lineage consisting of clonal complex 5 that emerged in the early 1970s. The success of the two lineages is partly attributed to two independent acquisitions of the mecA-carrying mobile element SCCmec and other resistance genes. Genome-wide association analysis revealed other sequence elements associated with methicillin resistance, but these also vary between the two lineages. We conclude that the SAB population was shaped mainly by the clonal expansion and co-dominance of two lineages with distinct genomic features and evolutionary histories. Future surveillance is essential for documenting the long-term dynamics of drug resistant SAB, including the potential for less common lineages to increase in frequency in the population.