According to the US Centers for Disease Control and Prevention (CDC), an estimated 107,543 deaths due to unintentional drug overdose occurred in the US in 2023. People who use drugs are also at increased risk of infection (e.g., HIV; hepatitis A, B, and C; bacterial skin infections; endocarditis). To decrease the morbidity and mortality associated with drug use, this article outlines harm reduction strategies clinicians can discuss to optimize safety when people who use drugs are not prepared to abstain from use. These strategies include safer supply; overdose prevention; medications to decrease risk of HIV infection; methods to decrease risk of hepatitis A, B, and C infections; and for patients who inject drugs, safer injection and injection alternatives. https://jamanetwork.com/journals/jama/article-abstract/2826345?resultClick=1&asam.org