Abstract Raising farm animals involves a variety of exposures, including microbes, antimicrobial agents, bioaerosols, and pesticides that may influence the human microbiome. Exposure to farm animals has also been associated with some cancers including lower risk of lung cancer and elevated risks of certain hematologic malignancies, with heterogeneity by animal species. Increasing epidemiologic evidence suggests that changes in the oral microbiome contribute to cancer development. Few human studies have investigated the potential influence of farm animal exposures on the oral microbiome. We investigated associations between farm animal exposures and the oral microbiome in 1245 Iowa and North Carolina farmers and spouses from the Agricultural Health Study. Participants provided information on types and numbers of farm animals raised in telephone interviews close to the time of oral wash sample collection. DNA was extracted from oral wash specimens and analyzed using 16S rRNA gene (V4 region) sequencing. We evaluated associations between farm animal exposures and alpha diversity metrics [e.g., observed amplicon sequence variants (ASVs)] using linear regression and assessed differences in beta diversity metrics (e.g., weighted Unifrac) using permutational multivariate analysis of variance. In addition, we evaluated associations with the presence and relative abundance of specific genera using zero-inflated negative binomial regression. All analyses adjusted for potential confounders (e.g., sex, age, state of residence, smoking). Overall, 63% of participants reported raising any animals, most commonly cattle (46%) and hogs (20%). Raising sheep/goats was associated with lower alpha diversity [e.g., 18 (95% confidence interval: 3-33) fewer observed ASVs compared to not raising sheep/goats], with an exposure-response trend for increasing number of sheep/goats (13 and 24 fewer observed ASVs for 1-29 and ≥30 sheep/goats vs. none, respectively; Ptrend = 0.048). Increasing numbers of hogs and poultry were associated with higher and lower alpha diversity, respectively. Associations were similar after mutual adjustment for other farm animal types. Based on beta diversity analyses, we did not observe statistically significant differences in microbial compositions between participants with and without farm animals. After adjusting for multiple testing, having any farm animal was associated with an increased relative abundance of Porphyromonas, and several genera were more likely to be absent with specific animal exposures (e.g., Capnocytophaga for cattle and sheep/goats; Corynebacterium and Abiotrophia for sheep/goats). To our knowledge, this was the largest investigation of farm animal exposures and the human microbiome to date. Our preliminary findings suggest that animal farming may alter the oral microbiome and provide new insights into the potential role of animal exposures in cancer etiology. Citation Format: Vicky C. Chang, Vaishnavi Purandare, Rashmi Sinha, Gabriella Andreotti, Shilan Li, Xing Hua, Yukiko Yano, Kathryn R. Dalton, Mikyeong Lee, Christine G. Parks, Stephanie J. London, Dale P. Sandler, Mitchell H. Gail, Jianxin Shi, Jonathan N. Hofmann, Christian C. Abnet, Emily Vogtmann, Laura E. Beane Freeman. Farm animal exposures and the oral microbiome in the Agricultural Health Study [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 834.