Objectives: People experiencing homelessness (PEH) have been especially impacted by the COVID‐19 pandemic, likely due to increased vulnerabilities stemming from chronic diseases, substance use, and mental health conditions. Design: A case–control study to assess the presence of antibodies against SARS‐CoV‐2 among PEH and associations with key variables. Sample: A convenience sample of 97 PEH in Skid Row, Los Angeles. Measurements: A structured questionnaire assessing socio‐demographic, mental health, drug and alcohol use, health care access, pandemic stress, and other COVID‐19‐specific questions. Results: We found high anti‐receptor binding domain (RBD) IgG titers among five of 15 PEH who reported no prior COVID‐19 diagnosis or being vaccinated, suggesting undiagnosed and/or asymptomatic COVID‐19. While anti‐RBD IgG titers across vaccination categories were not statistically significant (p =.069), participants vaccinated with Janssen had the lowest mean anti‐RBD IgG titers. In multivariable analysis, we found negative associations between level of SARS‐CoV‐2 antibody titers with the Janssen vaccine and depression; thus, a need for integrated care for PEH with depression and COVID‐19. Conclusions: Further research is warranted to confirm the immune response, initial and over time, to SARS‐CoV‐2 infection and to COVID‐19 vaccinations, particularly among PEH whose immune systems may be impacted by multiple health conditions. [ABSTRACT FROM AUTHOR]