Abstract Introduction: The fraction of people living in unaffordable housing in the U.S. has grown, and prior studies have documented a relationship between housing cost burden and worsening health. Medicaid expansion has been suggested to improve housing financial stability by reducing health care costs and improving access to preventative care. However, the role of expanded access to Medicaid on the relationship between housing cost burden and cancer mortality remains poorly understood. We investigated the relationship between county-level severe housing cost burden and premature cancer mortality by state Medicaid expansion status for all cancers and leading sites. Methods: This ecological study used county-level data from 2016-2020 American Community Survey linked with county-level mortality data. Severe housing cost burden measured by percentage of households within a county that spend ≥50% of their income on housing categorized into quintiles (1=lowest, 5=highest) and state Medicaid expansion status (expanded and non-expanded). Age-adjusted cancer mortality rates and adjusted-mortality rate ratio (aRR) were estimated by sex. Results: Across quintiles of county-level severe housing cost burden, age-adjusted cancer mortality rates were largely greater in non-Medicaid expanded states than Medicaid expanded states among women and men. Among counties in the lowest quintile of severe housing cost burden, rates for overall cancer mortality in women were 9% (aRR=1.09; 95%CI 1.05-1.14) higher in non-Medicaid expanded states compared with expanded states. Additionally, among the third quintile of severe housing cost burden, colorectal cancer mortality rate was 8% higher (aRR=1.08; 95%CI 1.02-1.14) in non-Medicaid expanded states. Among men in the lowest quintile of severe housing cost burden, overall cancer mortality rates were 5% (aRR=1.05; 95%CI 1.02-1.09) higher in non-Medicaid expanded states than Medicaid expanded states. Further, among men in counties in the highest quintile of severe housing cost burden, colorectal cancer mortality rate was 8% higher (aRR=1.08; 95%CI 1.05-1.12) and lung cancer mortality was 13% higher (aRR=1.13; 95%CI 1.10-1.15) in non-Medicaid expanded states compared with expanded states. Conclusions: Counties with a lower fraction of households experiencing severe housing cost burden had greater premature cancer death rates within non-Medicaid expanded states than Medicaid expanded states. However, among men rates were also elevated in non-Medicaid expanded states in counties with the greatest severe housing cost burden. Citation Format: Wayne R. Lawrence, Neal D. Freedman, Jennifer K. McGee-Avila, Lee Mason, Yingxi Chen, Aldenise P. Ewing, Meredith S. Shiels. Severe housing cost burden and premature cancer mortality by state Medicaid expansion status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 801.