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Background: Although a third of gastroesophageal reflux disease (GERD) patients are refractory to proton pump inhibitor (PPI) therapy, the underlying mechanism of the refractoriness remains unclear. We compared the level of gastric acid suppression during PPI treatment between responders and non-responders by directly measuring gastric acid secretion in GERD patients taking PPIs. Methods: Seventy-five consecutive patients receiving standard-dose PPI therapy for GERD were prospectively recruited, irrespective of persistent GERD symptoms. They were asked about their GERD symptoms using a validated questionnaire, and simultaneously underwent both a routine endoscopic examination and a gastric acid secretory testing using an endoscopic gastrin test. Associations between residual gastric acid secretion during PPI treatment and persistent GERD symptoms were analyzed by a logistic regression analysis. Results: Overall, 26 of 75 (34.7%) patients were judged to be positive for persistent GERD symptoms. The patients with and without persistent symptoms showed similar gastric acid secretion levels (1.3 [1.3] mEq/10 min vs. 1.4 [2.0] mEq/10 min). Sufficient gastric acid suppression, defined as < 0.6, was not significantly associated with persistent GERD symptoms (odds ratio 1.1, 95% confidence interval 0.40–3.5). Conclusions: This study provided solid evidence to support that the gastric acid suppression level during PPI treatment does not differ between patients with and without persistent GERD symptoms. The insignificant role of residual gastric acid in the persistent GERD symptoms suggests that the use of medications other than those that enhance gastric acid inhibitory effects would be an essential approach for the management of PPI-refractory GERD. [ABSTRACT FROM AUTHOR]