Summary 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.