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Background Methicillin-resistant S. aureus (MRSA) is a common antibiotic-resistant human pathogen that spreads from person to person. Asymptomatic host colonization precedes both skin and soft tissue infections (SSTI) and bloodstream infections (BSI), but it is not known how closely related MRSA strains are that cause infections at different body sites. Methods Using Illumina whole genome sequencing, we compared the strain types and genomes of MRSA isolates from 132 SSTIs and 145 sequential BSIs at 3 Philadelphia hospitals in 7/2018-1/2021. We investigated the epidemiological links and genomic clusters among isolates causing BSI and SSTIs. Results Abscesses were the most common type of SSTIs (65/132, 49%). Clonal complex (CC) 8 was the most identified CC among both SSTI strains (102/132, 77%) and BSI strains (73/145, 50%). While CC5 was more commonly found among BSIs than SSTIs (50/145, 34% vs. 19/132, 13%). Outbreak clusters with 15 or fewer SNPs were identified. Three clusters that contained only strains from SSTIs were all CC8, and the five clusters that only contained strains from BSIs had three CC5 clusters and two CC8 clusters. Among eight clusters that included at least one SSTI and one BSI strain, only one was composed of CC5 and the others were all CC8 strains. Within these eight clusters the SSTIs were from cellulitis infections (4/8), an abscess (3/8), or an infected ulcer (1/8). Conclusion We found that CC8 strains were the most common among both SSTIs and BSIs. CC5 strains, however, were more commonly found in BSIs than SSTIs, and among outbreak clusters in the BSI strains. Eight outbreak clusters were identified that linked strains causing SSTIs or BSIs, seven of the clusters contained only CC8 strains. While abscesses were the most common infection type to cause an SSTI, within the outbreak clusters containing strains from both SSTIs and BSIs, both cellulitis and abscess were equally identified. Disclosures Michael Z. David, MD PhD, Contrafect: Grant/Research Support|GSK: Advisor/Consultant|Johnson and Johnson: Advisor/Consultant.