BACKGROUND: Per-and polyfluoroalkyl substances (PFAS) are widely used, environmentally ubiquitous, and stable chemicals that have been associated with lower vaccine-induced antibody responses in children; however, data on adults are limited. The drinking water from one of the two water-works in Ronneby, Sweden, was heavily contaminated for decades with PFAS from firefighting foams, primarily perfluorohexane sulfonic acid and perfluorooctanesulfonic acid (PFOS). Vaccination against SARS-CoV-2 offered a unique opportunity to investigate antibody responses to primary vaccination in adults who had been exposed to PFAS. OBJECTIVES: Our objective was to evaluate associations between PFAS, across a wide range of exposure levels, and antibody responses in adults 5 wk and 6 months after a two-dose vaccination regime against SARS-CoV-2. METHODS: Adults age 20–60 y from Ronneby (n = 309, median PFOS serum level 47 ng=mL, fifth to 95th percentile 4–213 ng=mL) and a group with background exposure (n = 47, median PFOS serum level 4 ng=mL) received two doses of the Spikevax (Moderna) mRNA vaccine. The levels of seven PFAS were measured in serum before vaccination. Serum immunoglobulin G antibodies against the SARS-CoV-2 spike antigen (S-Abs) were measured before vaccination and at 5 wk (n = 350) and 6 months (n = 329) after the second vaccine dose. Linear regression analyses were fitted against current, historical, and prenatal exposure to PFAS, adjusting for sex, age, and smoking, excluding individuals with previous SARS-CoV-2-infection. RESULTS: PFAS exposure, regardless of how it was estimated, was not negatively associated with antibody levels 5 wk [current PFOS: −0:5% S-Abs/ PFOS interquartile range (IQR); 95% confidence interval (CI): −8, 7] or 6 months (current PFOS: 3% S-Abs/PFOS IQR; 95% CI: −6, 12) after COVID-19 vaccination. DISCUSSION: Following a strict study protocol, rigorous study design, and few dropouts, we found no indication that PFAS exposure negatively affected antibody responses to COVID-19 mRNA vaccination for up to 6 months after vaccination. https://doi.org/10.1289/EHP11847.