Background <p>Several studies have documented racial and ethnic disparities related to SARS-CoV-2/COVID-19 prevalence and associated health outcomes, but the proximal determinants underpinning these disparities remain unclear. Here, we test whether demographics, household composition, occupation type, chronic conditions, health insurance coverage, and neighborhood disadvantage account for racial and ethnic inequities in COVID-19 outcomes.</p> Methods <p>We conducted a serosurvey of adults in Chicago, IL (<i>n</i> = 5991) before emergency use authorization for COVID-19 vaccines in December 2020. Participants completed an online survey and provided a dried blood spot (DBS) sample for quantification of SARS-CoV-2 antibodies.</p> Results <p>Hispanic/Latino and Black participants had greater odds of being seropositive and being diagnosed with COVID-19 compared to White participants. Among seropositive participants, Hispanic/Latino and Black participants had higher antibody concentrations compared to White participants, and Hispanic/Latino participants had higher levels of symptom severity compared to White participants. Adding all variables to the model yielded a statistically significant reduction in the magnitude of Hispanic/Latino vs. White disparities in symptom severity among seropositive participants (Δ = − 59.4%, <i>P</i> = 0.015). We detected spatial clustering of high symptom severity in predominantly Hispanic/Latino neighborhoods and low symptom severity in predominantly White neighborhoods. Multiple inequities remained apparent after adjustment for all covariates.</p> Conclusions <p>Household composition, demographics, occupation type, chronic conditions, and neighborhood disadvantage collectively explain a substantial proportion of Hispanic/Latino vs. White inequities in symptom severity, but these factors are not sufficient to explain racial and ethnic inequities in SARS-CoV-2 seropositivity and COVID-19 case rates.</p>