Background: Eosinophilic esophagitis (EoE) is a recently defined chronic immune-mediated disease of atopic etiology with esophageal dysfunction and mucosal eosinophilic infiltrate. Among esophageal high-resolution manometry (HRM) parameters, intrabolus pressure (IBP) has shown the possibility to distinguish patients with mucosal inflammation, who benefit from proton pump inhibitors (PPI), from those with initial fibrosis and lack of response to treatment. In this study, we aimed to identify biomarkers able to identify which group a patient belongs to and obtain an early response. Methods: Combining diagnostic and esophageal function tests, proteomic and histological immunohistochemical analysis we studied 24 patients with EoE to extrapolate a protein profile from biopsies of the middle third of the esophagus analysis. Among them, 20 patients also underwent esophageal HRM. Results: IBP values were found to be significantly different among the controls, responsive and non-responsive patients, in relation to PPI treatment. Proteomic analysis identified 1,445 proteins, 456 shared between the two groups of patients, with 58 proteins identified as differentially expressed (DEPs) between the two groups of patients. Among all identified proteins, we found that, by immunohistochemistry, Gal-3 was overexpressed in patients’ responder to PPI, and with image analysis the difference between the two groups was statistically significant (% positive cells p<0.01, % positive area p<0.005) Conclusions: This study showed the chance of knowing forward the response to PPI therapy, improving patients’ personalized therapy and quality of life.