Objective: To examine the association between county-level Black-White residential segregation and COVID-19 vaccination rates. Design: Observational cross-sectional study using multivariable generalized linear models with state fixed effects to estimate the average marginal effects of segregation on vaccination rates. Setting: National analysis of county-level vaccination rates. Main Outcome Measure: County-level vaccination rates across the United States. Results: We found an overall positive association between county-level segregation and the proportion population fully vaccinated, with a 6.8, 11.3, and 12.8 percentage point increase in the proportion fully vaccinated by May 3, September 27, and December 6, 2021, respectively. Effects were muted after adjustment for sociodemographic variables. Furthermore, in analyses including an interaction term between the county proportion of Black residents and the county dissimilarity index, the association between segregation and vaccination is positive in counties with a lower proportion of Black residents (ie, 5%) but negative in counties with the highest proportions of Black residents (ie, 70%). Conclusions: Findings highlight the importance of methodological decisions when modeling disparities in COVID-19 vaccinations. Researchers should consider mediating and moderating factors and examine interaction effects and stratified analyses taking racial group distributions into account. Results can inform policies around the prioritization of vaccine distribution and outreach.