AbstractTo date, COVID-19 case rates are disproportionately higher in Black and Latinx communities across the U.S., leading to more hospitalizations and deaths in those communities. These differences in case rates are evident in comparisons of Chicago neighborhoods with differing race/ethnicities of their residents. Disparities could be due to neighborhoods with more adverse health outcomes associated with poverty and other social determinants of health experiencing higher prevalence of SARS-CoV-2 infection or due to greater morbidity and mortality resulting from equivalent SARS-CoV-2 infection prevalence. We surveyed five pairs of adjacent ZIP codes in Chicago with disparate COVID-19 case rates for highly specific and quantitative serological evidence of any prior infection by SARS-CoV-2 to compare with their disparate COVID-19 case rates. Dried blood spot samples were self-collected at home by internet-recruited participants in summer 2020, shortly after Chicago’s first wave of the COVID-19 pandemic. Pairs of neighboring ZIP codes with very different COVID-19 case rates had similar seropositivity rates for anti-SARS-CoV-2 receptor binding domain IgG antibodies. Overall, these findings of comparable exposure to SARS-CoV-2 across neighborhoods with very disparate COVID-19 case rates are consistent with social determinants of health, and the comorbidities related to them, driving differences in COVID-19 rates across neighborhoods.