Background: Genetic areas of FOXP3 TSDR, HLA-G upstream of CpG island 96, CpG41 and CpG73 islands of the HLA‐DRB1 and HLA-DQB1 genes respectively, previously documented to display immune modulatory properties, were subjected to epigenetic/genetic analysis to assess their influence in IgE-mediated food allergy (FA) development in children. Methods: 64 orally challenged and IgE- tested food allergic subjects together with 44 controls were recruited. Targeted pyrosequencing analysis, to detect DNA methylation status and genetic variations was utilized and experimental results obtained were analysed by statistical software platform and correlated to clinical data. Also, transcription factor (TF) binding sites at study areas were unmasked by the JASPAR prediction database. Results: Parents’ smoking was significantly correlated with aberrant methylation patterns, regardless food allergic or control status. HLA-G promoter region showed a trend for hypomethylation in food allergic subjects, with one of the CG sites displaying significantly decreased methylation values. Rs1233333, residing within HLA-G promoter region preserved a protective role towards DNA methylation. Variable methylation patterns were recorded for CpG41 of the HLA‐DRB1 gene and hypermethylation of the region was significantly correlated with the presence of (Single Nucleotide Polymorphisms) SNPs. TFs’ recognition sites, located at studied genetic areas and exerting pivotal regulatory biological roles, are potentially affected from divergent DNA methylation status. Conclusions: We propose that HLA-G expression is triggered by food derived allergens, providing a TregFoxP3-/HLA-G+ subpopulation generation and direct immune-tolerance. Furthermore, clear evidence is provided for the underlying co-operation of genetic polymorphisms with epigenetic events, mainly at CpG41 island of HLA-DRB1 gene, which need an extended investigation and elucidation.