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• This study is the first large-sample prospective cohort study to examine the association between placental inflammatory cytokines mRNA expression and preschoolers' behavioral problems. • In preschool boys, a positive association between placental pro-inflammatory chemokines IL-8 mRNA levels and CBCL scores on anxious/depressed problems, aggressive behaviors, externalizing problems and total problems is observed. • In preschool girls, medium levels of pro-inflammatory cytokines (CRP, IL-6, IL-1β) seems to be associated with a decreased risk of some behavioral problems (emotionally reactive problems, externalizing problems, withdrawal) compared to high or low levels. • For anti-inflammatory cytokines, medium levels of IL-4 are found to be associated with a low risk of externalizing problems in preschool girls and medium levels of IL-10 were related to a low risk of internalizing problems in preschool boys, compared to low levels. Placental inflammation may contribute to brain abnormalities and childhood neuropsychiatric disorders, but limited knowledge is available on the association of placental inflammatory cytokine levels and offspring's behavioral development. This study aimed to examine the sex-specific association between placental inflammatory cytokine mRNA expression and preschoolers' behavioral development. 3474 pregnant women were recruited as the initial study population in the Ma'anshan birth cohort (MABC) study. Placentas (n = 2519) were collected during childbirth, and the mRNA expression of IL-8, IL-1β, CRP, TNF-α, IL-6, IL-10, and IL-4 was assessed. The Child Behavior Checklist 1.5–5 (CBCL 1.5–5) was used to assess children's behavioral development at 4 years old. A T-score ≥ 60 on summary scales or a score ≥ 65 on syndrome scales was regarded as the borderline clinical range. Multiple linear regression models and binary logistic regression models were applied to explore the sex-specific associations between placental inflammatory cytokines mRNA transcript levels and preschoolers' behavioral development. Sex-specific associations between placental inflammatory cytokines mRNA expression and preschoolers' behavioral development were observed. There was a positive association between IL-8 and CBCL scores for boys on anxious/depressed problems, aggressive behaviors, externalizing problems and total problems. Logistic regression models showed that high levels of IL-8 were associated with a higher risk of girls' emotionally reactive problems and sleep problems compared to low/medium levels. High TNF-α was correlated with increased sleep problem scores in boys, and medium TNF-α (vs. low levels) was associated with an increased risk of girls' externalizing problems. Medium levels of CRP, IL-1β, and IL-6 were found to be associated with a decreased risk of girls' behavioral problems compared to low/high levels. For anti-inflammatory cytokines, medium IL-10 and IL-4 (vs. low levels) were observed to be associated with a lower risk of internalizing problems in boys and externalizing problems in girls, respectively. High IL-10 was correlated with decreased attention problem scores in boys. This study indicates that placental inflammatory cytokine mRNA expression of IL-8, CRP, TNF-α, IL-1β, IL-4 and IL-10 may be associated with preschoolers' behavioral development in a sex-specific manner. [ABSTRACT FROM AUTHOR]