Introduction: Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of Midline (MID)-1 and subsequent downregulation of Protein Phosphatase 2A (PP2A) but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Methods: Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild type and TRAIL deficient (Tnfsf10 -/-) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments OVA challenged mice were intraperitoneally administered salmeterol or dexamethasone. Results: Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation as compared to controls. Tnfsf10-/- mice with experimental EoE, were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13 and CCL11 when compared with wild type mice. Salmeterol administration to wild type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression and remodeling which was comparable to the treatment effect of dexamethasone. Conclusion: TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by Salmeterol.