BACKGROUND: It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort. METHODS: This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11 ng/ml, and FS as specific IgE >/= 0.35 kUA/l to any of eight common food allergens in early childhood. We genotyped potentially functional single-nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs. RESULTS: Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (p(interaction) = 0.003, p(FDR) = 0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR = 1.79, 95%CI: 1.15-2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (p(interaction) = 9 x 10(-6) ). CONCLUSIONS: Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.