INTRODUCTION: Prenatal exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) is ubiquitous among pregnant individuals. However, research exploring the relationship between prenatal co-exposure to OPEs and PAEs and childhood insulin function remains limited. METHODS: In this study, utilizing data from 2,246 maternal-fetal dyads in the Ma'anshan Birth Cohort, associations between co-exposure to OPEs and PAEs and insulin action were analyzed. Repeated measures of tris (2-chloroethyl) phosphate, six OPE metabolites, and seven PAE metabolites were collected from maternal urine. Homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin action index (IAI) served as outcome measures. After adjusting for potential confounders, the effects of repeated exposure on insulin action were evaluated using generalized estimating equations, while mixture effects were assessed through BayesianKernel Machine Regression and Quantile-Based G-Computation. RESULTS: The average age of the children at the time of the study was 5.33 years. Repeated measures analysis revealed that prenatal exposure to MEP was positively associated with increased HOMA-IR (β, 0.027
95 % CI: 0.002, 0.053), while IAI was inversely correlated with rising MEP levels (β, 0.025
95 % CI: -0.046, -0.004) and MEHHP exposure (β, -0.128
95 % CI: -0.218, -0.037). Mixed exposure modeling further indicated that co-exposure to OPEs and PAEs was positively linked to HOMA-IR (β, 0.058
95 % CI: 0.001, 0.114) and negatively correlated with IAI (β, -0.054
95 % CI: -0.097, -0.010), with stronger effects observed during the second trimester. Notably, the association was more pronounced in female children compared to males. CONCLUSIONS: This study provides the first epidemiological evidence highlighting the pregnancy- and sex-specific links between prenatal co-exposure to OPEs and PAEs and childhood insulin action.