Background: Recent series describing the clinical presentation, response to therapy, and long-term outcome of Zollinger-Ellison syndrome are limited. Aims: To assess the clinical characteristics and long-term outcome of patients with Zollinger-Ellison syndrome. Methods: Over a 20-year period, patients with Zollinger-Ellison syndrome were enrolled in a prospective trial evaluating the efficacy of lansoprazole. Following dose stabilization, patients were followed on a 6-monthly basis with interval history, physical examination, endoscopy with gastric biopsies, gastric acid analysis and laboratory studies. Results: 72 patients (mean age 54 ± 12 years, % male 58%, % Caucasian 69%) were prospectively enrolled. The clinical presentation was stereotypical for Zollinger-Ellison syndrome. Symptoms had been reported for a median of 9 years prior to diagnosis. Cross-sectional abdominal imaging was often negative for demonstrable tumour. All patients had gastric acid hypersecretion controlled with variable doses of lansoprazole (median dose 60. mg/day, range 15-480. mg/day). The median survival from the time of diagnosis was 6.6 years; only two of 19 deaths were due to metastatic gastrinoma. Conclusions: The clinical presentation of Zollinger-Ellison syndrome was similar to prior reports. Acid hypersecretion was controlled in all patients with variable doses of lansoprazole. Long-term survival was principally related to underlying co-morbidity. © 2010 Editrice Gastroenterologica Italiana S.r.l.