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Abstract Background We investigate the relationships among political preferences, risk for COVID-19 complications, and complying with preventative behaviors, such as social distancing, quarantine, and vaccination, as they remain incompletely understood. Since those with underlying health conditions have the highest mortality risk, prevention strategies targeting them and their caretakers effectively can save lives. Understanding caretakers’ adherence is also crucial as their behavior affects the probability of transmission and quality of care, but is understudied. Examining the degree to which adherence to prevention measures within these populations is affected by their health status vs. voting preference, a key predictor of preventative behavior in the U. S, is imperative to improve targeted public health messaging. Knowledge of these associations could inform targeted COVID-19 campaigns to improve adherence for those at risk for severe consequences. Methods We conducted a nationally-representative online survey of U.S. adults between May–June 2020 assessing: 1) attempts to socially-distance; 2) willingness/ability to self-quarantine; and 3) intention of COVID-19 vaccination. We estimated the relationships between 1) political preferences 2) underlying health status, and 3) being a caretaker to someone with high-risk conditions and each dependent variable. Sensitivity analyses examined the associations between political preference and dependent variables among participants with high-risk conditions and/or obesity. Results Among 908 participants, 75.2% engaged in social-distancing, 94.4% were willing/able to self-quarantine, and 60.1% intended to get vaccinated. Compared to participants intending to vote for Biden, participants who intended to vote for Trump were significantly less likely to have tried to socially-distance, self-quarantine, or intend to be vaccinated. We observed the same trends in analyses restricted to participants with underlying health conditions and their caretakers Underlying health status was independently associated with social distancing among individuals with obesity and another high-risk condition, but not other outcomes. Conclusion Engagement in preventative behavior is associated with political voting preference and not individual risk of severe COVID-19 or being a caretaker of a high-risk individual. Community based strategies and public health messaging should be tailored to individuals based on political preferences especially for those with obesity and other high-risk conditions. Efforts must be accompanied by broader public policy.