Abstract Body (Do not enter title and authors here): Introduction: Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. While coagulation system variation causes VTE, other novel biological pathways remain underexplored. This study aims to provide a comprehensive understanding of the plasma proteomics signature associated with genetic susceptibility for VTE, as captured by a polygenic risk score (PRS). Methods: We constructed a race-specific PRS for VTE for participants in the ARIC, an ongoing community-based prospective cohort, based on the two newest large genome-wide association studies (GWAS) reports: one reported 93 risk loci in individuals of European ancestry (PMCID: 36658437); another identified 135 risk loci from a cross-ancestry GWAS (36154123). We included 139 SNPs in the PRS calculation in ARIC European American (EA) and African American (AA) participants using SNP dosage and race-specific estimates when possible. A total of 4,955 plasma proteins were measured by SOMAscan v4 from samples collected at ARIC visit 2 in 1990-92. We then employed race-specific linear regression to associate the VTE PRS with levels of all 4,955 proteins, controlling for potential confounders. We treated the analysis in EAs (n=7,402) as discovery and that in AAs (n=1,933) as replication, applying Bonferroni correction to account for multiple testing. We then conducted pathway analysis using the Ingenuity Pathway (IPA) to identify enriched biological signaling pathways for the top PRS-protein associations based on FDR<0.01. Results: In the EA participants, 90 proteins were statistically significantly associated with the VTE PRS (p<5x10^-5). Among these, 15 were replicated in the AA participants (p<0.00056) with the consistent direction of associations and 7 of these 15 proteins at p<5x10^-5. Beyond the well-documented proteins for VTE, such as VWF and coagulation factors VIII, and XI, novel proteins were also identified, such as sulfhydryl oxidase 2, interleukin-3 receptor subunit alpha, ephrin type-A receptor 4, and insulin receptor. The IPA analysis indicated enrichment of the coagulation system, IL-15 pathways, and heparan sulfate biosynthesis pathways. Conclusion: This comprehensive proteomic analysis offers valuable insights into the circulating proteomics signature and biological pathways underlying the genetic predisposition for VTE, potentially enhancing our understanding of VTE etiology and prevention.