SummaryBackgroundExposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown.MethodsIn the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics.FindingsHigher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes.InterpretationsPrenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis.FundingAll funding received by COPSAC are listed onwww.copsac.com. The10.13039/501100003554Lundbeck Foundation(Grant no R16-A1694); The10.13039/501100009708Novo Nordic Foundation(Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764);The Ministry of Health(Grant no 903516);10.13039/100007398Danish Council for Strategic Research(Grant no 0603-00280B); and TheCapital Region Research Foundationhave provided core support to the COPSAC research center. COPSAC acknowledges theNational Facility for Exposomics(SciLifeLab, Sweden) for supporting calibration of the untargeted metabolomics PFAS data. BC and AS has received funding for this project from the10.13039/501100007601European Union’s Horizon 2020research and innovation programme (BC: grant agreement No. 946228 DEFEND; AS: grant agreement No. 864764 HEDIMED).