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The typical symptoms of gastroesophageal reflux disease (GERD) are heartburn and regurgitation. Extensive analysis has characterized heartburn and its responsiveness to proton pump inhibitor (PPI) therapy, but regurgitation has received relatively little attention. This study aimed to evaluate the response of regurgitation to PPI therapy in GERD trials.Studies were identified by systematic searches in PubMed and Embase, as well as searching congress abstracts and the reference lists of Cochrane reviews.Regurgitation was not an entry criterion or the primary end point in any of the 31 clinical trials reporting the response of regurgitation to PPI treatment in GERD. The definitions of regurgitation and responsiveness varied among trials and over half used investigator assessment of response. Owing to these inconsistencies, no meta-analysis was attempted. In seven placebo-controlled trials of PPI therapy, the therapeutic gain for regurgitation response averaged 17% relative to placebo and was >20% less than that observed for heartburn. Studies comparing PPIs with histamine-2 receptor antagonists or prokinetics found the comparator drug response similar to the placebo response rates seen in the placebo-controlled trials.The therapeutic gain with PPIs over placebo or comparator agents for the relief of regurgitation is modest, and considerably lower than for heartburn. Thus, regurgitation is likely to be an important factor for determining incomplete response to PPI treatment in GERD. Future trials would benefit from using regurgitation as a primary end point, applying an unambiguous definition of the symptom and of a positive treatment response, and using a validated patient-reported instrument for regurgitation assessment.