Food allergy (FA) affects 2%–10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10⁻⁸) and rs9275596 (P=6.8 × 10⁻¹⁰), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 × 10⁻⁸), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP–PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA.