AbstractThe neuropeptide oxytocin (OXT) and its receptor (OXTR) modulate interpersonal relationships, particularly mother–child interactions. DNA methylation (DNAm) changes of theOXTRgene were observed in individuals who experienced Childhood Maltreatment (CM). A modulatory role of single nucleotide polymorphisms (SNP) withinOXTRin association with CM on the regulation of OXTR was also postulated. Whether these CM-induced epigenetic alterations are biologically inherited by the offspring remains unknown. We thus investigated possible intergenerational effects of maternal CM exposure on DNAm andOXTRgene expression, additionally accounting for the possible influence of three SNP: rs53576 and rs2254298 (OXTRgene), and rs2740210 (OXTgene). We used theChildhood Trauma Questionnaireto classify mothers into individuals with (CM+) or without CM (CM−). Maternal peripheral immune cells were isolated from venous blood (N = 117) and fetal immune cells from the umbilical cord (N = 113) after parturition. DNA methylation was assessed using MassARRAY. Taqman assays were performed for genotyping and gene expression analyses. Among mothers, CM was not associated withOXTRmean methylation or gene expression. However, four CpG sites showed different methylation levels in CM− compared to CM+. In mothers, theOXTRrs53576 andOXTrs2740210 allelic variations interacted with CM load on theOXTRmean methylation. Maternal and newborns’ mean methylation ofOXTRwere positively associated within CM− dyads, but not in CM+ dyads. We show gene×environment interactions on the epigenetic regulation of the oxytocinergic signaling and show the intergenerational comparability of theOXTRDNAm might be altered in infants of CM+ mothers.