BACKGROUND: Ultra-processed foods account for >
50% of total energy consumed among U.S. individuals and may be a source of poly- and perfluoroalkyl substances (PFAS) exposure - chemicals linked with cancer/cardiometabolic disorders. OBJECTIVE: To evaluate associations between degree of food processing and PFAS exposure. METHODS: Serum concentrations of seven PFAS were analyzed in 11,530 individuals ≥12-years-old from the U.S. National Health and Nutrition Examination Survey (2003-2018). We averaged responses from two 24-h dietary recalls to calculate relative energy intakes of unprocessed/minimally processed foods, processed culinary ingredients, processed foods, and ultra-processed foods using the Nova food classification system. We estimated percent differences in concentrations (β
PFAS with ≥70% detection) or odds ratios of detection (OR
PFAS with <
70% detection) using linear or logistic regression, respectively. We explored associations stratified by cycle, life stage, sex, body mass index, race/ethnicity, and poverty/income ratio. RESULTS: Each 10% increase in ultra-processed food intake was associated with higher serum perfluorohexanesulfonic acid (PFHxS
β: 1.40
95%CI: -0.12, 2.94), but lower perfluorodecanoic acid (PFDA
β: -4.41
95%CI: -5.55, -3.26) and perfluoroundecanoic acid (PFUnDA
OR: 0.82
95%CI: 0.79, 0.86) concentrations. Positive associations between ultra-processed foods and PFHxS were driven by adolescents and under-/normal weight individuals. Additionally, each 10% increase in unprocessed/minimally processed food intake was associated with lower perfluorooctanoic acid (PFOA
β: -1.10
95%CI: -2.38, 0.20) and PFHxS (β: -1.50
95%CI: -3.03, 0.06), but higher perfluorononanoic acid (PFNA
β: 1.71
95%CI: 0.24, 3.21), PFDA (β: 5.33
95%CI: 3.78, 6.90), and PFUnDA (OR: 1.22
95%CI: 1.16, 1.27). Positive and negative associations of unprocessed/minimally processed foods and ultra-processed foods, respectively, with PFDA and PFUnDA were strongest in recent survey cycles, males, and non-Hispanic Asians. SIGNIFICANCE: Unprocessed/minimally processed foods, more than ultra-processed, were associated with serum PFAS concentrations. Efforts should focus on eliminating PFAS from multiple parts of the food chain.