Abstract Objective: We examined total polyphenol intake and intake of polyphenol classes and subclasses with risk of lung cancer in the Southern Community Cohort Study (SCCS). Background: In the US, lung cancer incidence is highest in the south and among underrepresented and underserved populations. Diet is strongly associated with the risk of developing cancer, including lung cancer. Polyphenols, commonly found in plant-based foods, are biologically active compounds with antioxidant and other properties. Several population-based studies have found that higher intakes of some polyphenols were associated with a decreased risk of lung cancer, but this has not been studied in predominantly Black or low-income populations, nor have polyphenol classes and subclasses been studied extensively. Methods: The SCCS is a large, prospective cohort study established in 2002-2009 to study the causes of cancer disparities in 12 southern states. Two-thirds of the cohort are Black and over 50% have an annual household income less than $15,000. Diagnosis of lung cancer was obtained from state cancer registries and death records. Polyphenol intakes derived from a food frequency questionnaire assessing diet in the previous year were adjusted for total energy intake and grouped into quintiles. Cox proportional hazard models adjusted for potential confounders were used to estimate hazard ratios and 95% confidence intervals to determine associations between polyphenol intakes and lung cancer risk. Multiple imputation was performed to account for participants with incomplete information. After exclusions, analyses included 71,569 participants, including 1,484 incident lung cancer cases. Results: Total polyphenols were associated with a statistically significant increased risk of lung cancer (HR, 1.25; 95% CI, 1.04-1.51; P=0.01, comparing the highest to lowest intake quintile). Additionally, three subclasses (phenolic acids, hydroxycinnamic acids, alkylmethoxyphenols) were associated with a similarly statistically significant increased risk of lung cancer. Most associations were similar between Black and White individuals but were largely only statistically significant among Black participants and there was no significant interaction by race. In stratified analysis by smoking status, the associations were primarily present among current and former smokers. Caffeinated or decaffeinated coffee consumption was a major contributor to intake of total polyphenols, phenolic acids, hydroxycinnamic acids, and alkylmethoxyphenols for SCCS participants overall. Conclusions: Total polyphenols and three subclasses of polyphenols were unexpectedly associated with increased lung cancer risk. Further studies should be conducted to evaluate whether some polyphenols may have an adverse effect on lung carcinogenesis, particularly among individuals who smoke. Citation Format: Grace Xu, Heather Munro, Danxia Yu, Qi Dai, Martha Shrubsole. Dietary polyphenols and the risk of lung cancer in the prospective Southern Community Cohort Study [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 A019.