BACKGROUND: Homeless people have a higher risk of COVID-19 infection, linked to several social, economic and environmental determinants, frequent comorbidities, obstacles to exercising their constitutional social and health rights, poor medical cover, and insufficient use of the healthcare system. Data on COVID-19 vaccine uptake and its main determinants are lacking for this underserved population. OBJECTIVES: To construct and test a conceptual framework to model structural social determinants of COVID-19 vaccine uptake among underserved homeless populations, and to test this model to identify the determinants of COVID-19 vaccine uptake on the homeless population living in two metropolitan areas in France. METHODS: We implemented a multicenter cross-sectional survey from 15/11/2021 to 22/12/2021 in homeless adults in the city of Marseille and in the greater Paris area. Persons sheltered in migrant worker hostels or in emergency social shelters, members of the COVID HOMELESS cohort study in Marseille, and Travelers living in traditional housing were all eligible. A standardized face-to-face questionnaire was administered to the participants where they lived in various languages by trained interviewers. We used structural equation modeling to analyze the structural social determinants of COVID-19 vaccine uptake, the latter defined as receiving at least one dose. RESULTS: The participation rate was 64 %, accounting for 3811 participants. There were three main factors associated with greater vaccine uptake: i) opportunity, which included having a personal general practitioner (β = 0.05, p < 0.05), healthcare cover (β = 0.05, p < 0.05), and somebody to accompany the participant for medical appointments (β = -0.04, p < 0.05); ii) motivation, which included attitudes towards vaccination (β = 0.55, p < 0.05), press- and poster-based information (β = 0.03, p < 0.05), and vaccination history (β = 0.03, p < 0.05); iii) type of housing (β = 0.13, p < 0.05) and housing stability (β = 0.04, p < 0.05). CONCLUSION: Our results highlight that housing exclusion is a structural social determinant of COVID-19 vaccine uptake in homeless people in France. They also underline the role which opportunity and motivation play in improving uptake in this underserved homeless population.< Réduire