Abstract Background: It remains unclear why African Americans (AA) have higher incidence of non-small cell lung cancer (NSCLC) and develop the disease 5 years earlier than Non-Hispanic Whites (NHW). Studies suggest that residential segregation drives NSCLC mortality disparities; however, there has been little investigation into whether residential segregation is also linked to the increased incidence of NSCLC risk among AAs. The lack of clarity regarding this link limits our understanding of possible societal determinants (SDH) related etiologies of the deadly disease. We aimed to evaluate the relationship between the isolation index – a well-known racial residential segregation metric that measures the level of exposure an average member of a specific demographic has with its own demographic – and NSCLC risk among AAs. We hypothesize that residential segregation will be associated with NSCLC risk in AAs but not in NHWs. Methods: We analyzed data from the Southern Community Cohort Study (SCCS), a large, prospective observational cohort study that recruited over 80,000 participants in the southeastern US from 2002-2009. The primary outcome is the NSCLC incidence. The SCCS is linked with cancer registries across the 12-state geographic catchment area, enabling the identification of NSCLC incidence. The isolation index was calculated using 2010 census tract data and ranges from 0 to 1, with a higher score representing higher isolation. The subdistribution hazard of NSCLC risk with the isolation index was estimated using Fine-Gray subdistribution hazard models, adjusted by demographic factors, smoking status and secondhand smoke exposure – all obtained from participant self-report surveys. Results: Of the 53,820 AA participants (mean age 50, 59% female, 37% never smokers), 1272 (2.4%) were diagnosed with NSCLC since enrollment. Of the 24,778 NHW participants (mean age 53, 61% female, 34% never smokers), 742 (3.0%) were diagnosed with NSCLC. Mean isolation index for AA = 0.71 (SD = 0.26), NHW= 0.25 (SD = 0.25). We found a significant association between residential segregation, as measured by the isolation index, and time to NSCLC in AAs. The adjusted subdistribution Hazard Ratio (sHR) of NSCLC risk for AAs with a 0.1 increase in isolation index was 1.03 (95% CI: 1.01, 1.05, p = 0.01). We did not detect a significant association in NHWs (p=0.88). The interaction between race and isolation index was not significant which may be due to lack of power. Conclusion: Our study is one of the first to document a link between racial residential segregation and NSCLC risk in AAs. This finding suggests that residential segregation, instituted and implemented by structural racism, embodies an environment that elevates NSCLC risk in AAs. Evaluation of structural racism across domains beyond segregation, in addition to the use of robust spatiotemporal methods, is required to further clarify the link with SDH, including structural racism and NSCLC risk. Such studies are essential to informing policies and interventions to improve population health and cancer prevention. Citation Format: Xiaoke Zou, Calvin Tribby, Richard Curley, Melinda Aldrich, Sophia Wang, Kimlin Ashing, Rick Kittles, Lennie Wong, Tarik Benmarhnia, Marta Jankowska, Loretta Erhunmwunsee. Residential segregation contributes to non-small cell lung cancer risk in African Americans in the southeastern US [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C089.