Substance use-related harms including drug overdose deaths and new cases of human immunodeficiency virus (HIV) and hepatitis C (HCV) are increasing in the US. Syringe services programs (SSPs) started in the 1980s as community-based efforts to distribute sterile syringes and provide safe injection information to people who inject drugs (PWID) in response to rising HIV infection rates. SSPs are guided by harm reduction principles, which aim to mitigate the negative consequences of drug use. The term SSP broadly refers to the provision of sterile syringes and other supplies and is inclusive of any setting that provides these supplies for the intended injection of drugs. The present report is an attempt to provide an overall picture of what is known about the benefits and potential harms of SSPs, which has been an active area of research for the past 4 decades. This report was requested by the VA Offices of Mental Health and Suicide Prevention, Research and Development, and Specialty Care Services to inform VA efforts to meet the goals of the Office of National Drug Control Policy and to implement best practices for harm reduction in VHA settings.