BackgroundCOVID-19 mortality studies have primarily focused on persons aged ≥ 65 years; less is known about decedents aged <65 years.MethodsWe conducted a case-control study among NYC residents aged 21–64 years hospitalized with COVID-19 diagnosed March 13–April 9, 2020, to determine risk factors for death. Case-patients (n=343) were hospitalized decedents with COVID-19 and control-patients (n=686) were discharged from hospitalization with COVID-19 and matched 2:1 to case-patients on age and residential neighborhood. Conditional logistic regression models were adjusted for patient sex, insurance status, and marital status. Matched adjusted odds ratios (aORs) were calculated for selected underlying conditions, combinations of conditions, and race/ethnic group.ResultsMedian age of both case-patients and control-patients was 56 years (range: 23–64 years). Having ≥ 1 selected underlying condition increased odds of death 4.45-fold (95% CI: 2.33–8.49). Patients with diabetes; morbid obesity; heart, kidney, or lung disease; cancer; neurologic/neurodevelopmental conditions; mental health conditions; or HIV had significantly increased odds of death. Compared with having neither condition, having both diabetes and obesity or diabetes and heart disease was associated with approximately threefold odds of death. Five select underlying conditions were more prevalent among non-Hispanic Black control-patients than among control-patients of other races/ethnicities.Conclusions and RelevanceSelected underlying conditions were risk factors for death, and most prevalent among racial/ethnic minorities. Social services; health care resources, including vaccination; and tailored public health messaging are important for COVID-19 prevention. Strengthening these strategies for racial/ethnic minority groups could minimize COVID-19 racial/ethnic disparities.