ObjectivesThe objective of this study was to examine COVID-19 vaccination acceptance and explore reasons for COVID-19 vaccine hesitancy among people who use drugs (PWUDs), a population with increased COVID-19 transmission and morbidity.MethodsWe conducted semi-structured in-depth interviews with PWUDs in 7 Oregon counties from May 11 to June 25, 2021. Participants (n = 34) were recruited in partnership with syringe service programs and local community organizations staff, participant-referrals, and flyer advertising. Research staff conducted interviews via telephone to assess participants’ acceptance of the COVID-19 vaccine, find knowledge gaps where new educational information about vaccination would be helpful, and identify who would be perceived as a trustworthy source of information. Interviews were transcribed and coded using thematic analysis with a deductive approach.ResultsMost participants had not received the COVID-19 vaccine and were not planning on or were unsure about receiving it. Participants were mistrustful of the rapid COVID-19 vaccine development process, the agencies involved in the development, and vaccines in general. Participants shared varied and contrasting responses about who they would trust to provide information about the COVID-19 vaccine, including peer recovery support specialists, doctors, or other health care professionals, and specified federal agencies or media outlets.ConclusionsAs addiction medicine and public health staff continue to respond to the evolving impacts of COVID-19, vaccination planning should be tailored to the unique needs of PWUD to increase COVID-19 vaccine acceptance in this high-risk population.