Abstract Background: Oropharyngeal cancer (OPC) disparities exist across race-ethnicity, socioeconomic status, and sociobehavioral characteristics, as well as across different US regions. However, no investigations have interactively assessed these multilevel factors in the polarizing dynamics of region-specific political leanings and affiliated local policies. Methods: This retrospective ecological analysis used the NPCR-SEER database to evaluate county-area-summarized OPC age-adjusted annual mortality rates from 2000-2020 and the CDC-Social Vulnerability Index to assess 15 country-level SDH-vulnerability factors across all 3143 US counties. OPC-mortality rates for White, Black, and all race-ethnic groups were regionally stratified based on the Presidential and midterm (categorized into Democrat, Republican) electoral results of their counties’ respective states for each biannual cycle. These stratified mortality rates were regressed against socioeconomic status, minority-language status, household composition, housing-transportation SDH-vulnerabilities, as well as their total composite. Results: Across the US, yearly age-adjusted OPC-mortality mean rate was 2.94 deaths/100k patients from 2000 to 2020, with counties in Republican-leaning states having higher mortality rates (3.09/100k) compared to Democratic ones (2.72/100k). Mortality rates for Black patients were substantially higher in Republican-leaning areas (4.02/100k) than Democratic ones (3.08/100k). Non-Hispanic white patients also showed lesser increases in mortality in Republican-areas (3.04/100k) compared to Democratic ones (2.68/100k). With increasing total SDH-vulnerability, white populations in Republican-leaning areas suffered 0.27 age-adjusted added deaths/100k annually & 0.22/100k in Democratic ones, whereas black populations in Republican states suffered 0.51/100k annually & 0.34/100k in Democratic ones. For white patients, vulnerabilities in socioeconomic status primarily contributed to these mortality disparities in Democratic-leaning areas while both socioeconomic status and household composition vulnerabilities influenced disparities in Republican ones. For black patients, household composition primarily contributed in Democratic areas, whereas socioeconomic status, housing-transportation, and household composition-vulnerabilities all contributed equivalently in Republican ones. Conclusions: The results of this study showcase multilevel, population effects of political leanings and racial-ethnic demographic makeup in conferring SDH-derived OPC-mortality disparities over the past two decades. In particular, black OPC patients from Republican-leaning areas suffered exacerbated associations of SDH-vulnerability-related disparities driven by varied SDH-types. Through this nuanced modeling of the interactions between geopolitical and sociodemographic factors, targeted public health resource allocation and policy-lobbying can more specifically address local legislature through this systematic, large-data approach. Citation Format: David J. Fei-Zhang, Mary J. Xu, Jeffrey C. Rastatter, Anthony M. Sheyn, Daniel C. Chelius, Jill N. D'Souza, Sandeep Samant, Urjeet A. Patel, Caryn E. Peterson, Olga Garcia-Bedoya, Patrick D. Smith, Kate Klein, Mamoudou Maiga, Warren A. Kibbe, Lifang Hou. Geopolitical and racial-ethnic trends of social vulnerability impact on oropharyngeal cancer mortality in the United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C004.