Background: Political orientation, particularly Republican vote share, has emerged as a key determinant of COVID-19 mortality in the United States. While previous research has shown the correlation between political ideology and preventative health behaviors, the causal relationship between the two has been more difficult to show. Our study uses the change in political ideology of the Republican Party across COVID-19 waves as a method of testing whether, and when, political orientation impacts on preventive health behavior. Methods: We analyze COVID-19 mortality data from 3,108 U.S. counties across 60 fortnights, employing multilevel negative binomial regression to assess the relationship between Republican vote share and COVID-19 deaths. We compare the effects of Republican vote share across four pandemic waves and use dose-response and falsification tests to evaluate for specificity and causal inference. Main Results: During Wave 1 (February–August 2020), Republican vote share did not have a significant association with COVID-19 mortality (IRR = 1.07; [1.00, 1.14]; p > 0.05, not significant), reflecting the administration’s initial focus on pandemic prevention and anti-China rhetoric. However, in the later Waves, the association of Republican vote and COVID-19 mortality strengthened significantly (Wave 2: IRR = 1.28; [1.23, 1.33]; Wave 3: IRR = 1.14; [1.10, 1.18]; Wave 4: IRR = 1.17; [1.14, 1.21]) as the Republican Party became oppositional to public health measures like lockdowns, social distancing, mask-wearing and vaccination. The relationship between Republican vote and COVID-19 mortality shows a dose-response relationship and Republican vote had inconsistent relationships with other public health outcomes. Discussion: These findings provide strong evidence that political ideology can impact large scale mortality rates. The differential impact of Republican vote across different waves of COVID-19, the dose-response relationship between Republican vote and COVID-19 mortality, and the small impact of Republican vote on other health outcomes, suggests the relationship is causal, and linked to the specific anti-public health ideologies of the Republican Party in the 2nd, 3rd, and 4th waves of COVID-19.

COVID-19, Republican Vote, Mortality, Political Ideology, Pandemic Waves