Abstract We reexamined our experience with the surgical and medical management of 53 patients with Zollinger-Ellison syndrome due to gastrinoma during the past decade. Surgical “cure” (defined here as resection of all identifiable tumor with normalization of serum gastrin and gastric secretory variables) appeared possible in 7 patients (of 44 explored, or 16%). Five of the 7 “cured” patients had duodenal wall tumors. Currently, these 7 receive no therapy, and none has apparent metastasis or multiple endocrine neoplasia, type 1. Excluding patients who have metastasis or multiple endocrine neoplasia, type 1 by preoperative screening would have increased the relative chance of surgical “cure” from 16% to 20% (7 of 35). Patients with unresectable or recurrent gastrinomas had a much worse prognosis than did patients whose tumors did not recur after resection or patients with a negative laparotomy. In any case, therapy with H 2-receptor antagonists offered a satisfactory fallback position for management of gastric hypersecretion and its consequences. Adequate control by their use was achieved in 16 of 18 patients who were followed up an average of 28.9 mo (range 7–59 mo) without major side effects. Total gastrectomy, while undoubtedly the most effective therapy of gastric hypersecretion, is not free of significant sequelae, as evidenced by long-term follow-up of 18 gastrectomized patients. We concluded that (a) patients with Zollinger-Ellison syndrome without multiple endocrine neoplasia, type 1 or metastasis should undergo exploratory laparotomy and potential resection of identifiable gastrinomas; (b) chronic therapy with H 2-receptor antagonists is preferable to total gastrectomy and satisfactory control may be achieved in most patients, and (c) tumor death is currently the major threat to survival for patients with unresectable gastrinomas, particularly nonmultiple endocrine neoplasia, type 1.