Abstract Background The opioid epidemic has resulted in a dramatic resurgence of bacterial infections, most notably those due to Staphylococcus aureus (SA). We compared the demographic, clinical, and molecular factors of injection drug users (IDUs) and non-IDUs with SA bacteremia. Methods Patients with SA bacteremia were identified through a query of the electronic medical record EMR from January 2018 to December 2019 at a New York City medical center. All cases of community-associated (CA) SA bacteremia among adults with a history of active injection drug use were evaluated. Patients with positive SA blood cultures ≤ 72 hours of admission were considered CA. IDUs were identified with keyword searches and were deemed active if they had a history of use in the 12 months prior to admission. A randomly selected group of non-IDUs with CA SA bacteremia was used for comparison at a 4:1 ratio. Available SA isolates underwent Illumina whole genome sequencing (WGS). Using SRST2 multilocus sequence types (MLST), antimicrobial resistance genes and putative virulence factors were extracted. Results From January 2018 to December 2019, 669 patients with SA bacteremia were identified. 29 patients were active IDUs. Compared to 112 randomly selected non-IDUs, IDUs were significantly younger and more likely to be unstably housed (Table 1). Rates of MRSA were similar in IDUs (31%) and non-IDUs (32.1%). Endocarditis (44.8% vs 11.6%) and abscesses (27.6% vs 8.9%) were diagnosed more frequently in IDUs than non-IDUs. A positive hepatitis C antibody was strongly associated with SA bacteremia in IDUs (62.1% vs 6.3%, p< 0.001). WGS demonstrated comparable proportions of sequence types across IDUs and non-IDUs. ST8 accounted for the majority of infections in both groups (Table 2). MRSA bacteremia due to ST8 occurred in a higher proportion of IDUs (7/29, 24.1%) than non-IDUs (14/112, 12.5%). Conclusion IDUs with CA SA bacteremia have unique demographic and clinical features that differentiate them from non-IDUs. Endocarditis rates in IDUs are of particular concern. Use of these risk factors could allow hospitals to rapidly identify IDUs and offer them necessary medical and social services. WGS revealed a majority of MRSA bacteremia was due to one sequence type in IDUs (ST8). Further analysis of virulence genes in this cohort are ongoing. Disclosures Franklin D. Lowy, MD, GlaxoSmithKline (Advisor or Review Panel member)UpToDate (Other Financial or Material Support, Topic Writer and Editor) Anne-Catrin Uhlemann, MD, PhD, Merck (Grant/Research Support)