Immune-specific genes as well as genes responsible for the formation and integrity of the epidermal barrier have been implicated in the pathogeneses of allergic sensitization. This study sought to determine whether an epistatic effect (gene-gene interaction) between genetic variants within interleukin 4 receptor (IL4R) and filaggrin (FLG) genes predispose to the development of allergic sensitization. Data from two birth cohort studies were analyzed, namely the Isle of Wight (IOW; n = 1,456) and the Manchester Asthma and Allergy Study (MAAS; n = 1,058). In the IOW study, one interaction term (IL4R rs3024676 × FLG variants) showed statistical significance (interaction term: P = 0.003). To illustrate the observed epistasis, stratified analyses were performed, which showed that FLG variants were associated with allergic sensitization only among IL4R rs3024676 homozygotes (OR, 1.97; 95% CI, 1.27-3.05; P = 0.003). In contrast, FLG variants effect was masked among IL4R rs3024676 heterozygotes (OR, 0.53; 95% CI, 0.22-1.32; P = 0.175). Similar results were demonstrated in the MAAS study. Epistasis between immune (IL4R) and skin (FLG) regulatory genes exist in the pathogenesis of allergic sensitization. Hence, genetic susceptibility towards defective epidermal barrier and deviated immune responses could work together in the development of allergic sensitization.