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Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development.We tested for gene-environment interaction between EoE-predisposing polymorphisms (withinTSLP,LOC283710/KLF13,CAPN14,CCL26, andTGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home).We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE.Case-only analyses identified interactions between rs6736278(CAPN14)and breast-feeding (P= .02) and rs17815905(LOC283710/KLF13)and NICU admission (P= .02) but not with any of the factors examined. Case-control analyses suggested that disease risk might be modifiable in subjects with certain gene variants. In particular, breast-feeding in those with the susceptibility gene variant at rs6736278(CAPN14)reduced the risk of EoE (adjusted odds ratio, 0.08; 95% CI, 0.01-0.59). Admission to the NICU in those without the susceptibility gene variant at rs17815905(LOC283710/KLF13)significantly increased the risk of having disease (adjusted odds ratio, 4.83; 95% CI, 1.49-15.66).The interplay of gene(CAPN14andLOC283710/KLF13) and early-life environment factors (breast-feeding and NICU admission) might contribute to EoE susceptibility.