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Background & Aims: Exposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. Methods: In this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. Results: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 μg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. Conclusion: This proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings. Lay summary: Per- and polyfluoroalkyl substances (PFAS), often referred to as “forever chemicals” because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.