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Tailored public health messaging encouraging COVID-19 vaccination may help increase vaccination rates and decrease the burden of COVID-19. We conducted a three-part COVID-19 vaccine uptake public health campaign disseminated on Facebook between April and June 2021. Our first campaign focused on reaching Black and Latinx communities; our second campaign focused on addressing vaccine access and scheduling in Latinx communities; and our third campaign focused on religious communities. Overall, we reached 25 million individuals with 171 million views across the United States. ( Am J Public Health . 2022;112(9):1253-1256. https://doi.org/10.2105/AJPH.2022.306934).