Background: Persons experiencing unstable housing – including recently arrived migrants – are at elevated risk of contracting COVID-19 and suffer from high morbidity and mortality. In this context, the COVID-19 vaccine was foreseen as a promising way to control the pandemic and reduce social inequalities in this area. Understanding the motives of COVID-19 vaccine acceptability in people with unstable housing, including migrants, is therefore crucial to tailor public health communication and outreach. Thus, the main objective of our study was to investigate - both quantitatively and qualitatively – the motivations behind vaccine hesitancy in people experiencing unstable housing when vaccines became available in France.Methods: A cross-sectional study was performed in Spring 2021, using convergent mixed-methods approach. Participants were recruited from homeless shelters and day centres and face-to-face interviews were offered, with help, where necessary, from phone-based interpreters. Factors associated with motives for COVID-19 vaccine hesitancy were explored using logistic regression models. Qualitative data – collected through semi-structured individual interviews - were analysed via an inductive thematic approach. Both quantitative and qualitative data were then integrated. Results: Vaccine hesitancy was found to be at an elevated rate (58.0%). The three most reported motives of hesitancy were related to COVID-19 vaccine effectiveness, safety, and trust in information about the vaccine. Factors of elevated hesitancy comprised the interviewees’ age, level of education, French-language aptitude, feeling of worry about COVID-19, and time of residence in France. Generic distrust in official information was a shared associated factor for the 3 motives of hesitancy. This result was expanded upon by the interview data where participants described having differential trust depending on who is recommending the vaccination. Another emerging key theme related to hopes that the vaccine would release them from the burden of the pandemic. Conclusions: Our mixed methods study provides a comprehensive understanding of COVID-19 vaccine hesitancy among persons with unstable housing in France in Spring 2021. Elevated levels of hesitancy remain a public health concern as “No one is safe until everyone is safe”. The already established role of trust in vaccine hesitancy is still to be adequately addressed as a potentially effective route of intervention.