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Understanding the effects of widespread disruption of the social fabric on public health outcomes can provide insight into the forces that drive major political realignment. Our objective was to estimate the association between increases in mortality in middle-aged non-Hispanic white adults from 1999 to 2005 to 2009–2015, health inequalities in life expectancy by income, and the surge in support for the Republican Party in pivotal US counties in the 2016 presidential election. We conducted a longitudinal ecological study in 2764 US counties from 1999 to 2016. Increases in mortality were measured using age-specific (45–54 years of age) all-cause mortality from 1999 to 2005 to 2009–2015 at the county level. Support for the Republican Party was measured as the party's vote share in the presidential election in 2016 adjusted for results in 2008 and 2012. We found a significant up-turn in mortality from 1999 to 2005 …