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Objectives: Uncovering and addressing disparities in infectious disease outbreaks require a rapid, methodical understanding of local epidemiology. We conducted a seroprevalence study of SARS-CoV-2 infection in Holyoke, Massachusetts, a majority Hispanic city with high levels of socio-economic disadvantage to estimate seroprevalence and identify disparities in SARS-CoV-2 infection. Methods: We invited 2000 randomly sampled households between 11/5/2020 and 12/31/2020 to complete questionnaires and provide dried blood spots for SARS-CoV-2 antibody testing. We calculated seroprevalence based on the presence of IgG antibodies using a weighted Bayesian procedure that incorporated uncertainty in antibody test sensitivity and specificity and accounted for household clustering. Results: Two hundred eighty households including 472 individuals were enrolled. Three hundred twenty-eight individuals underwent antibody testing. Citywide seroprevalence of SARS-CoV-2 IgG was 13.1% (95% CI 6.9–22.3) compared to 9.8% of the population infected based on publicly reported cases. Seroprevalence was 16.1% (95% CI 6.2–31.8) among Hispanic individuals compared to 9.4% (95% CI 4.6–16.4) among non-Hispanic white individuals. Seroprevalence was higher among Spanish-speaking households (21.9%; 95% CI 8.3–43.9) compared to English-speaking households (10.2%; 95% CI 5.2–18.0) and among individuals in high social vulnerability index (SVI) areas based on the CDC SVI (14.4%; 95% CI 7.1–25.5) compared to low SVI areas (8.2%; 95% CI 3.1–16.9). Conclusions: The SARS-CoV-2 IgG seroprevalence in a city with high levels of social vulnerability was 13.1% during the pre-vaccination period of the COVID-19 pandemic. Hispanic individuals and individuals in communities characterized by high SVI were at the highest risk of infection. Public health interventions should be designed to ensure that individuals in high social vulnerability communities have access to the tools to combat COVID-19.