AbstractBackground: Per- and polyfluoroalkyl substances (PFASs) including perfluorooctanoic acid (PFOA) are ubiquitous environmental contaminants. Prior analysis in the large “C8 Health Project” population defined abnormal alanine aminotransferase (ALT) with statistically derived cutoffs (>45 IU/L in men, >34 IU/L in women). Objective: To explore the degree to which PFOA was associated with modern, clinically predictive ALT biomarker cutoffs in obese and nonobese participants, excluding those with diagnosed liver disease. Methods: We reevaluated the relationship of serum PFOA to abnormal ALT using predictive cutoff recommendations including those of the American College of Gastroenterology (ACG). Evaluations modeled lifetime cumulative exposure and measured internal PFOA exposure. Results: ACG cutoff values (≥34 IU/L for males, ≥25 IU/L for females) classified 30% of males (3815/12,672) and 21% of females (3359/15,788) above ALT cutoff values. Odds ratios (OR) for above cutoff values were consistently associated with modeled cumulative and measured serum PFOA. Linear trends were highly significant. ORs by quintile showed near monotonic increases. Trends were stronger for the overweight and obese. However, all weight classes were affected. Conclusion: Predictive cutoffs increase the OR for abnormal ALT results. Obesity increases ORs, yet association with abnormal ALT pertains to all weight classes. The results are discussed in context of current knowledge about the health implications of PFOA hepatotoxicity.