<title>Abstract</title>The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in <italic>PPARA</italic> (rs1800234; rs135561), <italic>PPARG</italic> (rs3856806), <italic>PPARGC1A</italic> (rs2970847; rs8192678), <italic>PPARD</italic> (rs1053049; rs2267668), <italic>CAR</italic> (rs2307424; rs2501873), <italic>LXRA</italic> (rs2279238) and <italic>LXRB</italic> (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log₁₀ scale) decreased palmitic, palmitoleic, and oleic acid levels (log₁₀ scale), with the observed β in the range of − 0.452 to − 0.244; <italic>PPARGC1A</italic> (rs8192678) and <italic>PPARD</italic> (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed β in the range of − 0.266 to − 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (<italic>P</italic>_{<italic>int</italic>} = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and <italic>PPARGC1A</italic> or <italic>PPARD</italic> may modify maternal FA levels.