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Background The molecular basis and effects of proton pump inhibitor ( PPI) therapy on PPI-responsive oesophageal eosinophilia ( PPI- REE) and eosinophilic oesophagitis (EoE) remain unknown. Aim To compare symptom-histological and cytokine gene expression in PPI- REE and EoE patients, at baseline and after specific treatment. Methods In consecutive adult patients with an EoE phenotype (dysphagia/food impaction, typical endoscopic findings and > 15 eos/ HPF), gene expression of eotaxin-3, IL-13, and IL-5 were determined in distal and proximal oesophagus, at baseline and after omeprazole 40 mg b.d. for 8 weeks. PPI- REE was defined by clinicohistological response. PPI nonresponders (EoE) were offered treatment with topical steroids. Results Fifty three patients were re-evaluated on PPI therapy. 23 patients (43%) had PPI- REE and 30 patients (57%) had EoE. At baseline, eotaxin-3/ IL-13/ IL-5 gene expression was indistinguishable between EoE and PPI- REE, excepting increased IL-5 expression in proximal oesophagus (12.54 vs. 57, P = 0.029). PPI therapy significantly decreased eotaxin-3/ IL-13 in PPI- REE, at both oesophageal sites ( P ≤ 0.008), and IL-5 in distal ( P = 0.016), but not in proximal oesophagus. Patients with steroid-responsive EoE also showed a significant decrease in eotaxin-3/ IL-5 expression at both oesophageal sites. In EoE patients, initial PPI trial significantly decreased distal oesophageal eosinophilia (63.78 to 41.79 eos/ HPF, P = 0.025) and led to symptom remission in 16%, but did not influence Th2 markers. Conclusions Baseline cytokine gene expression in PPI- REE was nearly indistinguishable from EoE. PPI therapy significantly downregulated oesophageal eotaxin-3/Th2-cytokine gene expression in PPI- REE, similarly to that seen in steroid-responsive EoE. A subset of EoE patients showed clinicohistological improvement on PPI therapy. [ABSTRACT FROM AUTHOR]