BACKGROUNDDuring the early phases of the COVID-19 pandemic, predominantly African-American or Hispanic communities were disproportionately impacted. We sought to better understand the epidemiology of COVID-19 among hospitalized Hispanic patients by comparing individual and census-tract level characteristics of patients diagnosed with COVID-19 to those diagnosed with influenza, another viral infection with respiratory transmission. We evaluated the temporal changes in epidemiology across race-ethnicity related to a shelter-in-place mandate. METHODSWe evaluated patients hospitalized at Cook County Health, the safety-net health system for the Chicago metropolitan area. Among self-identified hospitalized Hispanic patients, we compared those with influenza (2019-2020 influenza season) to COVID-19 infection during March 16, 2020 through May 11, 2020. We used multivariable analysis to identify differences in individual and census-tract level characteristics between the two groups. RESULTSRelative to non-Hispanic blacks and whites, COVID-19 rapidly increased among Hispanics during promotion of social-distancing policies. Whereas non-Hispanic blacks were more likely to be hospitalized for influenza, Hispanic patients predominated among COVID-19 infections (40% relative increase compared to influenza). In the comparative analysis of influenza and COVID-19, Hispanic patients with COVID-19 were more likely to reside in census tracts with higher proportions of residents with the following characteristics Hispanic; no high school diploma; non-US citizen; limited English speaking ability; employed in manufacturing or construction; and, overcrowding. By multivariable analysis, Hispanic patients hospitalized with COVID-19 compared to those with influenza were more likely to be male (adjusted OR=1.8; 95% CI 1.1 to 2.9) or obese (aOR=2.5; 95% CI 1.5 to 4.2), and to reside in a census tract with [≥]40% of residents without a high-school diploma (aOR=2.5; 95% CI 1.3 to 4.8). CONCLUSIONSThe rapid and disproportionate increase in COVID-19 hospitalizations among Hispanics after the shelter-in-place mandate indicates that public health strategies were inadequate in protecting this population. In particular, those residing in neighborhoods with lower levels of educational attainment.