Links between HIV and substance use were identified early in the U.S. HIV epidemic. People who use drugs are at risk of HIV infection through shared injection equipment and risky sexual behaviors. In addition, substance use has negative health consequences for people living with HIV. The prescription opioid misuse epidemic, linked to injection drug use, hepatitis C infection, and HIV, poses a new threat to declining HIV rates. We reviewed evidence-based interventions that decrease HIV risk in people who use drugs (needle/syringe programs, medication-assisted treatment, engagement in HIV care, and preexposure prophylaxis/postexposure prophylaxis). The critical roles of nurses in HIV prevention/care for this population are described, including applying the principles of harm reduction, screening for substance use, and undertaking implementation and research efforts. As the nation's largest health care profession, nurses are positioned to contribute to the quality of HIV-related prevention/care for people who use drugs and to lead practice initiatives.