BACKGROUND: There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined. OBJECTIVE: We examined type 2 immunity-associated gene expression in esophageal biopsies aiming to determine the degree of cytokine heterogeneity and its potential clinical significance. METHODS: Patients (n=312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). In addition to histologic and endoscopic assessment, esophageal biopsies were examined for expression of 96 genes within the EoE Diagnostic Panel (EDP). RESULTS: Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, CCL26, TSLP, CLC, CCR3, and CPA3. These groups differed in age (P < 0.02) and EDP score (P <1.08E-30) but not eosinophil levels. Group V patients had the highest expression of IL5, TSLP, CCL26, and genes associated with tissue remodeling such as COL8A1, ACTG2 and TSPAN12. IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs. 14 years, P < 0.001). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III. CONCLUSION: We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.