A s a result of the epidemic of opioid use disorder (OUD), there has been a secondary surge in hospitalizations for infectious complications of injection drug use (IDU). 1,2 In the previous 10 years, there have been significant increases in IDU-associated human immunodeficiency virus (HIV) 3 and hepatitis C virus (HCV) 4 infection as well as increased hospitalizations from IDU-associated skin and soft tissue infections, osteomyelitis, septic arthritis, bacteremia, fungemia, and infective endocarditis in the United States. 2,[5][6][7] Patients admitted with IDU-associated infections have long lengths of stay, high rates of leaving against medical advice (AMA), readmission, and mortality. [8][9][10][11][12][13] In a British cohort (median age 36 years), five-year mortality after an episode of IDU-associated endocarditis was 42%. 14 Admissions for IDU-associated infections can be a troubling experience for both patients and providers alike. 15 While management decisions of IDU-associated infectious syndromes have sometimes been based on emotion, dogma, and an often-stigmatizing approach toward people suffering from addiction, 16 with a better understanding of addiction and effective treatments, as well as accumulating data in both addiction and infectious disease fields, it is an appropriate time to reevaluate the approach to treatment.The goal of this review is to examine recent evidence and attempt to answer questions that frequently arise in the management of hospitalized patients with IDU-associated infections. The questions addressed in this review primarily stem from the discussion of Schranz and colleagues in their description of increasing hospitalizations for IDU-associated endocarditis. 7 Additionally, questions were developed from discussions with practicing academic hospitalists. For each question, a review of the published literature was performed, with a focus on articles published between 2014 and 2019. Finally, a framework for how to approach patients with infectious complications of IDU is presented. As a comprehensive review of infectious complications of OUD would be difficult to cover in one review, this review will focus on eight questions that frequently arise in the care of inpatients.