Aim: To elucidate the mechanisms that lead to severe hypergastrinaemia during long-term omeprazole therapy for gastro-oesophageal reflux disease (GERD). Patients and methods: A total of 26 GERD patients were studied during omeprazole maintenance therapy. Twelve patients with severe hypergastrinaemia (gastrin > 400 ng/L) were compared with 14 control patients (gastrin < 300 ng/L). Helicobacter pylori serology and a laboratory screen were obtained in all patients. Gastric emptying was scored by the evidence of food remnants upon endoscopy 12 h after a standardized meal. Gastric antrum and corpus biopsies were analysed for histological parameter, as well as somatostatin and gastrin concentrations. All patients underwent a meal-stimulated gastrin test and the hypergastrinaemia patients also underwent a vagal nerve integrity assessment by pancreatic polypeptide testing (PPT). Results: Severe hypergastrinaemia patients had a longer duration of treatment (80 vs, 55 months; P = 0.047) and were characterized by a higher prevalence of H. pylori infection (9/12 vs, 2/14, P = 0.004), corpus mucosal inflammation and atrophic gastritis (P < 0.04). This was reflected in lower serum pepsinogen A concentrations (mean ± S.E.M. 53.6 ± 17.9 vs. 137 ± 16.0 mg/L, P = 0.03), pepsinogen A/C ratio (1.8 ± 0.3 vs, 4.1 ± 0.6, P = 0.005) and mucosal somatostatin concentrations (2.75 ± 0.60 vs, 4.48 ± 1.08 mg/g protein, P = 0.038). Two patients in the hypergastrinaemia group had signs of delayed gastric emptying, but none in the normogastrinaemia group did (P = N.S.). In addition, both groups had a normal meal-stimulated gastrin response, Conclusion: Severe hypergastrinaemia during omeprazole maintenance therapy for GERD is associated with the duration of therapy and H. pylori infection, but not with abnormalities of gastric emptying or vagal nerve integrity.