BACKGROUND: Despite many studies reporting disparities in coronavirus disease-2019 (COVID-19) incidence and outcomes in Black and Hispanic/Latino populations, mechanisms are not fully understood to inform mitigation strategies. OBJECTIVE: The aim was to test whether neighborhood factors beyond individual patient-level factors are associated with in-hospital mortality from COVID-19. We hypothesized that the Area Deprivation Index (ADI), a neighborhood census-block-level composite measure, was associated with COVID-19 mortality independently of race, ethnicity, and other patient factors. RESEARCH DESIGN: Multicenter retrospective cohort study examining COVID-19 in-hospital mortality. SUBJECTS: Inclusion required hospitalization with positive SARS-CoV-2 test or COVID-19 diagnosis at three large Midwestern academic centers. MEASURES: The primary study outcome was COVID-19 in-hospital mortality. Patient-level predictors included age, sex, race, insurance, body mass index, comorbidities, and ventilation. Neighborhoods were examined through the national ADI neighborhood deprivation rank comparing in-hospital mortality across ADI quintiles. Analyses used multivariable logistic regression with fixed site effects. RESULTS: Among 5999 COVID-19 patients median age was 61 (interquartile range: 44-73), 48% were male, 30% Black, and 10.8% died. Among patients who died, 32% lived in the most disadvantaged quintile while 11% lived in the least disadvantaged quintile; 52% of Black, 24% of Hispanic/Latino, and 8.5% of White patients lived in the most disadvantaged neighborhoods.Living in the most disadvantaged neighborhood quintile predicted higher mortality (adjusted odds ratio: 1.74; 95% confidence interval: 1.13-2.67) independent of race. Age, male sex, Medicare coverage, and ventilation also predicted mortality. CONCLUSIONS: Neighborhood disadvantage independently predicted in-hospital COVID-19 mortality. Findings support calls to consider neighborhood measures for vaccine distribution and policies to mitigate disparities.