Objectives The aim of this study was to determine the risk factors associated with SARS-CoV-2 infection in a cohort of homeless people using survival analysis. Seroprevalence in the homeless community was also compared with that of the general population. Design Cohort study. Setting Data were collected across two testing sessions, 3 months apart, during which each participant was tested for anti-SARS-CoV-2 antibodies and completed a face-to-face survey. Participants All homeless adults sleeping rough, in slums or squats, in emergency shelters or transitional accommodation in Marseille were eligible. Primary outcome measures Occurrence of a seroconversion event defined as a biologically confirmed SARS-CoV-2 infection. Local data from a national seroprevalence survey were used for comparison between homeless people and the general population. Results A total of 1249 people were included. SARS-CoV-2 seroprevalence increased from 6.0% (4.7-7.3) during the first session to 18.9% (16.0-21.7) during the second one, compared with 3.0% (1.9-4.2) and 6.5% (4.5-8.7) in the general population. Factors significantly associated with an increased risk of COVID-19 infection were: having stayed in emergency shelters (1.93 (1.18-3.15)), being an isolated parent (1.64 (1.07-2.52)) and having contact with more than 5-15 people per day (1.84 (1.27-2.67)). By contrast, smoking (0.46 (0.32-0.65)), having financial resources (0.70 (0.51-0.97)) and psychiatric or addictive comorbidities (0.52 (0.32-0.85)) were associated with a lower risk. Conclusion We confirm that homeless people have higher infection rates than the general population, with increased risk in emergency shelters. There is growing evidence that, in addition to usual preventive measures, public policies should pay attention to adapt the type of accommodation and overall approach of precariousness. Trial registration number NCT04408131