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Abstract Background Injection drug use-related infections cause substantial morbidity and can be mitigated by harm reduction programs. The objective was to describe Tennessee's injection-related infection hospitalization burden to guide syringe service program expansion efforts. Method Injection-related infection hospitalizations were retrospectively evaluated from 2016 to 2023 using the Tennessee Hospital Discharge Data System. Injection-related infection criteria were met if discharge International Classification of Diseases, 10th Revision (ICD-10) codes indicated both drug use and an infection that could be introduced through injection. Hospitalization characteristics, including demographics (age, sex, race/ethnicity, county), charges, and main payor, were described using counts (%) and median (interquartile range [IQR]). Incidence was calculated using US Census Bureau midyear estimates. Results During 2016–2023, injection-related infections comprised 1.6% (n = 79 276) of 5 million hospitalizations, incurring 602 321 hospitalization days and $5.38 billion in charges. The main payor was most frequently public insurance (n = 43 448, 54.8%) and self-pay (n = 23 001, 29.0%). Bacteremia or sepsis was most often diagnosed (n = 45 105, 56.9%), followed by skin and soft tissue (n = 17 152, 21.6%), endocarditis (n = 7386, 9.3%), musculoskeletal (n = 6458, 8.1%), and other (n = 3175, 4.0%) infections. Endocarditis incurred the greatest episodic length of stay (median 8 days [IQR 4–17]) and charges (median $60 633.50 [IQR $29 238–$130 368]). The annual hospitalization rate peaked at 194.29 per 100 000 persons in 2018, plateaued, and then decreased to 186.38 per 100 000 persons in 2023. Eastern Tennessee, part of the Appalachia region, had the highest rates of injection-related infections. Conclusions Injection-related infection annual hospitalization rates since 2018 have plateaued. Expanded access to syringe service programs, particularly in eastern Tennessee, can help prevent these costly hospitalizations.