Background Vaccine uptake rates have been historically low in correctional settings. To better understand vaccine hesitancy in these high-risk settings, we explored reasons for COVID-19 vaccine refusal among people in federal prisons. Methods Three maximum security all-male federal prisons in British Columbia, Alberta, and Ontario (Canada) were chosen, representing prisons with the highest proportions of COVID-19 vaccine refusal. Using a qualitative descriptive design and purposive sampling, individual semi-structured interviews were conducted with incarcerated people who had previously refused at least one COVID-19 vaccine until data saturation was achieved. An inductive-deductive thematic analysis of audio-recorded interview transcripts was conducted using the Conceptual Model of Vaccine Hesitancy. Results Between May 19-July 8, 2021, 14 participants were interviewed (median age: 30 years; n = 7 Indigenous, n = 4 visible minority, n = 3 White). Individual-, interpersonal-, and system-level factors were identified. Three were particularly relevant to the correctional setting: 1) Risk perception: participants perceived that they were at lower risk of COVID-19 due to restricted visits and interactions; 2) Health care services in prison: participants reported feeling "punished" and stigmatized due to strict COVID-19 restrictions, and failed to identify personal benefits of vaccination due to the lack of incentives; 3) Universal distrust: participants expressed distrust in prison employees, including health care providers. Interpretation Reasons for vaccine refusal among people in prison are multifaceted. Educational interventions could seek to address COVID-19 risk misconceptions in prison settings. However, impact may be limited if trust is not fostered and if incentives are not considered in vaccine promotion.