Abstract Background: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most common cancer and third leading cause of cancer deaths worldwide. Hepatitis B and/or C virus, alcohol use, and obesity are main drivers of HCC incidence and prognosis, with risk higher among Black and Hispanic individuals and those with lower socioeconomic status. HCC etiology recently shifted from viral to non-viral-related causes, with up to 40% of HCC cases unexplained by known risk factors. Food insecurity (FI) is associated with several known and emerging HCC risk factors, including poor diet quality, obesity, and diabetes. However, there is limited data on whether FI is in fact a social determinant of HCC risk. In this study, we conducted a county-level cross-sectional analysis to examine whether FI is associated with HCC risk in the United States. Methods: We used the Surveillance Epidemiology and End Results 22 database to obtain county-level counts of HCC cases from 2018-2021 stratified by age (20-64, ≥65 years), sex (female, male), and race and ethnicity (non-Hispanic White, non- Hispanic Black, non-Hispanic Asian or Pacific Islander, non-Hispanic American Indian or Alaska Native, and Hispanic). We obtained county-level FI rates for the years 2018-2021 from Feeding America’s Map the Meal Gap and calculated the average rate over these years. FI rates were calculated using imputation methods that consider state- and county-level sociodemographic variables associated with FI. We obtained additional county-level variables from the Behavior Risk Factor Surveillance System for the years 2018-2021. We used multi- level Poisson regression models with robust standard errors to estimate the association between FI and HCC risk. Models specified county population size as the offset term, and random effects for states and counties. We examined models adjusted for age, sex, race, and ethnicity (Model 1), and further adjusted for county-level binge drinking, smoking, obesity, and diabetes rates (Model 2). We tested multiplicative effect modification by individual-level factors. Results: We included 38,986 cases of HCC diagnosed in 1,085 counties. The mean county-level FI rate was 12.9% (standard deviation (SD)=3.6%). Overall, a 1-SD increase in FI was associated with a 9% increase in HCC risk in Model 1 (incidence rate ratio (IRR)=1.09, 95% CI=1.04-1.15) and a 5% increase in risk in Model 2 (IRR=1.05, 95% CI=1.02-1.09). When stratified by race and ethnicity, FI was only associated with HCC risk in non-Hispanic Whites in Model 2 (IRR=1.07, 95% CI=1.03-1.11; interaction p-value=.05). When stratified by age, FI was only associated with HCC risk in the <65 years group (IRR=1.13, 95% CI=1.08-1.18; interaction p-value <.001). The association did not differ by sex. Conclusion: This study provides some of the first data linking FI to increased HCC risk, in particular early onset HCC. If confirmed in other studies, these findings support the need for interventions that screen for, prevent, and address FI in populations at increased risk for HCC. Citation Format: Rebecca D. Kehm, Chrystelle L. Vilfranc, Jasmine A. McDonald, Hui Chen Wu. County-level food insecurity and hepatocellular carcinoma risk: A cross-sectional analysis [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 PR002.