Fifty-five consecutive patients with Zollinger-Ellison syndrome who underwent exploratory laparotomies for gastrinoma resection were evaluated prospectively to determine the effect of gastrinoma resection on acid secretion and to establish criteria for safe and effective perioperative management of gastric acid hypersecretion. In 15 patients (27%) no tumor was found and postoperative serum gastrin, basal acid output (BAO), and maximal acid output (MAO) were unchanged. Twenty-one patients (38%) had gastrinomas resected and were biochemically cured. Median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 89%, 94%, 80%, and 43%, respectively, at 3-month follow-up in these patients. In 19 patients gastrinomas were resected, but patients were not cured, and median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 47%, 10%, 26%, and 25%, respectively. Forty percent of patients with gastrinoma resected and cured and 81% of patients with gastrinoma resected but not cured continued to hypersecrete acid (BAO greater than 10 mEq/hr) at 3- to 6-month follow-up. Acid control was managed perioperatively during gastrinoma resection by continuous intravenous infusion of H2 receptor antagonists at a dose established by preoperative titration to decrease acid output to less than 10 mEq/hr. Thirty patients were treated with cimetidine at a mean dose of 3.2 mg/kg/hr for a mean of 13.8 days. Twenty-one patients were treated with ranitidine at a mean dose of 1.1 mg/kg/hr for a mean of 8 days. No patients suffered any complications related to acid hypersecretion or side effects of the H2 antagonists. Patients undergoing gastrinoma resection can be managed safely by continuous infusion of H2 antagonists. Successful gastrinoma resection can reduce acid output, but even 40% of biochemically cured patients will continue to hypersecrete acid at short-term follow-up and will require continuation of antisecretory medication.