Per- and polyfluoroalkyl substances (PFAS) are associated with reduced vaccine immune response, though most observational studies have found no link to COVID-19 vaccine response. Residents of North Carolina's Cape Fear River Basin have elevated serum PFAS levels. We investigated the cross-sectional association between serum PFAS and anti-Spike SARS-CoV-2 IgG (anti-S IgG) levels among COVID-19-vaccinated adults (N = 330) from three communities of the GenX Exposure Study with elevated PFAS. Eligibility criteria included no prior COVID-19 diagnosis and receipt of ≥2 COVID-19 vaccinations, the most recent within 180 days of data collection (June–November 2021). Serum PFAS (liquid chromatography-high resolution mass spectrometry) and anti-S IgG (AdviseDx SARS-CoV-2 IgG II Assay) were measured. For five PFAS with >85 % sample detection, we built general linear models of log-transformed PFAS and anti-S IgG for each community, adjusting for age, sex, and days since last vaccination. Most participants were mid-aged, female, and White. COVID-19 vaccination patterns (i.e., doses, manufacturer) and anti-S IgG levels varied by community. Modest positive and negative estimates of PFAS−anti-S IgG relationships were observed across communities and PFAS. One community (Lower Cape Fear River region) had the largest, and only statistically significant, estimate: 0.31 % (95 % CI: 0.07 %–0.56 %) increase in anti-S IgG per 1 % increase in PFHpS (PFAS with lowest median concentration). We observed no consistent evidence linking higher serum PFAS to lower COVID-19 vaccine response, aligning with prior studies. Assessing PFAS exposure and COVID-19 vaccine response in observational studies is challenging. Longitudinal studies with serial antibody measurements, and vaccine type considerations, might provide additional insight.

PFAS

SARS-CoV-2 IgG

COVID-19

Vaccination

© 2026 The Authors. Published by Elsevier GmbH.