Abstract Background: Black individuals with prostate cancer in the US experience the widest racial disparity in both cancer incidence and mortality when compared to the average population. These differences are driven by the intersection of race and a wide range of structural and social determinants of health and equity. Structural and social inequities can drive disproportionate and adverse exposure to violence, poverty, and physical and emotional stress—among other exposures—which may impact biologic risk, health behaviors, and healthcare access. We hypothesize that the impacts of these structural and social determinants are rooted in historical events that continue to inform present day prostate cancer events and outcomes. Methods: This is an ecological study assessing county-level data from 13 states in the Southeastern US. Data on prostate cancer incidence and mortality (NCI: 2018), population estimates (CDC: 2015-2019), structural and social determinants (AHRQ: 2018), and the percentage enslaved individuals (NHGIS: 1860) were obtained. County data were linked across datasets using federal identifiers. Our primary exposure was the legacy of US slavery represented by the percentage of enslaved individuals by county. Random variables such as water access and rail transport (NHGIS: 1860) were used as controls. Variable selection for our multivariable model was informed by a directed acyclical graph that defined the causal relationship between historical slavery and present-day prostate cancer outcomes. Our primary dependent variable was prostate cancer counts per 100,000. We utilized Poisson log-linear regression models to estimate the difference in cancer counts by 10% increase of slave population by county (NHGIS: 1860). Results: Our data included over 3000 counties. In our fully adjusted model, a 10% increase in county slave population was associated with a 1.5% increase in prostate cancer incidence (p<0.001). In this same model, Black race, and age (> 50 years) were associated with a 77% and over 300% increase in cancer incidence (p<0.001). Among Black men, every 10% increase in county slave population was associated with a 1.1% increase in cancer incidence (p < 0.05). Among White men, every 10% increase in county slave population was associated with a 1.5% increase in cancer incidence (p<0.0001). Our adjusted models demonstrated significant increased associations between prostate cancer incidence and education, access to food, segregation index, and social vulnerability index. Conclusions: Our results indicate that a history of slavery is significantly associated with increased county-level prostate cancer incidence for all men in the US, irrespective of their race/ethnicity. The effect of historic slavery persists even after adjusting for present day structural/social determinants of equity and health. These findings demonstrate the importance in acknowledging and incorporating historical inequities and context in evaluating present days inequities in prostate cancer risk, care, and outcomes. Citation Format: Maheetha C. Bharadwaj, Sarah C. Holt, Hari Iyer, John Gore, Tim Rebbeck, Yaw Nyame. County-level analysis of the link between historical slavery and prostate cancer incidence [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A091.