More than 750,000 persons in the United States inject opioids, methamphetamine, cocaine, or ketamine, and that number is increasing because of the current opioid epidemic. Persons who inject drugs (PWID) are at higher risk of infectious and noninfectious skin, pulmonary, cardiac, neurologic, and other causes of morbidity and mortality. Nonjudgmental inquiries about current drug use can uncover information about readiness for addiction treatment and identify modifiable risk factors for complications of injection drug use. All PWID should be screened for human immunodeficiency virus infection, latent tuberculosis, and hepatitis B and C, and receive vaccinations for hepatitis A and B, tetanus, and pneumonia if indicated. Pre-exposure prophylaxis for human immunodeficiency virus infection should also be offered. Naloxone should be prescribed to those at risk of opioid overdose. Skin and soft tissue infections are the most common medical complication in PWID and the top reason for hospitalization in these patients. Signs of systemic infection require hospitalization, blood cultures, and a comprehensive history and physical examination to determine the source of infection. PWID have a higher incidence of community-acquired pneumonia and are at risk of other pulmonary complications, including opioid-associated pulmonary edema, asthma, and foreign body granulomatosis. Infectious endocarditis is the most common cardiac complication associated with injection drug use and more often involves the right-sided heart valves, which may not present with heart murmurs or peripheral signs and symptoms, in PWID. Injections increase the risk of osteomyelitis, as well as subdural and epidural abscesses.