During the summer of 2021, a narrative of "two Americas" emerged: one with high demand for the COVID-19 vaccine and the second with widespread vaccine hesitancy and opposition to masks and vaccines. We analyzed “excess mortality” rates (the difference between total deaths and what would have been expected based on earlier time periods) prepared by the CDC for the United States from January 3, 2020 to September 26, 2021. Between Jan. 3, 2020 and Sept. 26, 2021, there were 895,693 excess deaths associated with COVID-19, 26% more than reported as such. The proportion of deaths estimated by the excess mortality method that was reported as COVID-19 was highest in the Northeast (92%) and lowest in the West (72%) and South (76%). Of the estimated deaths, 43% occurred between Oct. 4, 2020 and Feb. 27, 2021. Before May 31, 2020, approximately 56% of deaths were in the Northeast, where 17% of the population resides. Subsequently, 48% of deaths were in the South, which makes up 38% of the population. Since May 31, 2020, the South experienced COVID-19 mortality 26% higher than the national rate, whereas the Northeast’s rate was 42% lower. If each region had the same mortality rate as the Northeast, more than 316,234 COVID-19 deaths between May 31, 2020 and Sept. 26, 2021 were "avoidable." More than half (63%) of the avoidable deaths occurred between May 31, 2020 and February, 2021, and more than half (60%) were in the South. Regional differences in COVID-19 mortality have been strong throughout the pandemic. The South has had higher mortality rates than the rest of the U.S. since May 31, 2020, and experienced 62% of the avoidable deaths. A comprehensive COVID-19 policy, including population-based restrictions as well as vaccines, is needed to control the pandemic.