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SARS-CoV-2 vaccines provide significant protection against severe illness and death from COVID-19, in addition to reducing community transmission. Emerging research has identified factors associated with vaccine uptake among adults who use drugs; however, less is known about youth and young adults who use drugs (YWUD). To address this gap, we sought to characterize factors associated with vaccine uptake and explore vaccine hesitancy among YWUD. Data were derived from the At-Risk Youth Study, a prospective cohort of street-involved YWUD in Vancouver, Canada. Vaccine uptake was significantly lower among YWUD than adults who use drugs in Vancouver and the general population in British Columbia, among whom 75% and 93% received at least one dose during the same period. Study findings suggest connecting YWUD to healthcare and novel harm reduction interventions may increase vaccine uptake. Responses to vaccine hesitancy questions revealed complex perspectives of vaccines that were aligned with sources of vaccine hesitancy among the general population. Broader strategies combatting misinformation and promoting evidence-based vaccine information could be tailored to address the unique needs and barriers experienced by YWUD.