We report the case of a 22-year-old woman who was referred for evaluation of possible Zollinger-Ellison syndrome because of hypergastrinemia and a positive secretin stimulation test. She was being treated with proton pump inhibitors (PPIs) for severe gastroesophageal reflux disease during her initial evaluation. At cessation of PPI therapy, her fasting serum gastrin levels normalized, as did her response to secretin injection. Previous reports describing false-positive secretin tests have been limited to cases of hypergastrinemia in the setting of chronic atrophic gastritis, presumably a result of achlorhydria. This case represents a clearly documented instance of PPI-related hypergastrinemia with a false-positive secretin test, with subsequent normalization of serum gastrin and a negative secretin test after withdrawal of PPI therapy. The current case emphasizes the need to assess the acid secretory status of individuals with hypergastrinemia and to discontinue the use of potent antisecretory agents, principally PPIs, to avoid the erroneous diagnosis of gastrinoma and before embarking on expensive and potentially invasive evaluations for the purpose of tumor localization.