Background: Overcrowded housing, as well as inadequate sanitary conditions, contribute to making homeless people particularly vulnerable to the SARS-CoV-2 infection. We aimed to assess the seroprevalence of the SARS-CoV-2 infection among people experiencing homelessness on a large city-wide scale in Marseille, France, taking into account different types of accommodation. Methods: A consortium of outreach teams in 48 different locations including streets, slums, squats, emergency or transitional shelters and drop-in centres participated in the inclusion process. All participants consented to have a validated rapid antibody assay for immunoglobulins M (IgM) and G (IgG) and to answer a questionnaire on medical health conditions, comorbidities, and previous COVID-19 symptoms. Information on their housing conditions since the COVID-19 crisis was also collected from the participants. Results: From June 01 to August 05, 2020, 1,156 homeless participants were enrolled in the study and tested. The overall seroprevalence of SARS-CoV-2 IgG/IgM antibodies was 5.6% (95%CI 2.3-7.0), ranging from 2.2% in people living on the streets to 8.1% in people living in emergency shelters (P = 0.009). Around one third of the seropositive participants reported COVID-19 symptoms. Compared to the general population in Marseille (3.6%), the homeless population living in the same urban area experienced a significantly increased risk of SARS-CoV-2 infection (|z| = 3.65 > 1.96). Conclusion: These findings highlight the need for regular screening among the homeless to prevent clustering in overcrowded or inadequate accommodations. It is also necessary to provide essential resources to keep homeless people healthy, the vast majority of whom have cumulative risk factors for SARS-CoV-2 infection.