Objectives. To examine and compare how 4 indices of population-level social disadvantage-the Social Vulnerability Index (SVI), the Area Deprivation Index (ADI), the COVID-19 Community Vulnerability Index (CCVI), and the Minority Health-Social Vulnerability Index (MH-SVI)-are associated with COVID-19 outcomes. Methods. Spatial autoregressive models adjusted for population density, urbanicity, and state fixed effects were used to estimate associations of county-level SVI, MH-SVI, CCVI, and ADI values with COVID-19 incidence and mortality. Results. All 4 disadvantage indices had similar positive associations with COVID-19 incidence. Each index was also significantly associated with COVID-19 mortality, but the ADI had a stronger association than the CCVI, MH-SVI, and SVI. Conclusions. Despite differences in component measures and weighting, all 4 of the indices we assessed demonstrated associations between greater disadvantage and COVID-19 incidence and mortality. Public Health Implications. Our findings suggest that each of the 4 disadvantage indices can be used to assist public health leaders in targeting ongoing first-dose and booster or third-dose vaccines as well as new vaccines or other resources to regions most vulnerable to negative COVID-19 outcomes, weighing potential tradeoffs in their political and practical acceptability. (Am J Public Health. 2022;112(11):1584-1588. https://doi.org/10.2105/AJPH.2022.307018).