BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disor-ders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations.OBJECTIVES: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on child-hood obesity.METHODS: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), 0-hexachlorocyclohexane (0-HCH) and polychlori-nated biphenyls 138, 153, 180] and four per-and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n = 660), and b) OCs, PUFAs, and vitamins (n = 558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchi-cal group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and addi-tive scale. RESULTS: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vita-min B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, pInteraction = 0:02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooc-tane sulfonate and 0-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk.CONCLUSION: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/ obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epi-demiological studies. https://doi.org/10.1289/EHP11258