Background: Acid exposure time (AET) prolongation plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD). Gastric inhibitory polypeptide (GIP) and pancreatic polypeptide (PP) participate in the regulation of gastric acid secretion, blood glucose and lipid levels, and food intake. In this study, we evaluated the serum GIP and PP levels in refractory GERD patients and analyzed their metabolic and motility characteristics. Methods: Seventy-three refractory GERD patients were enrolled in this study from September 2015 to September 2017. We investigated the clinical characteristics, severity, and duration of GERD symptoms. High-resolution manometry and 24 hours impedance-pH monitoring were performed to assess esophageal motility and reflux parameters. The patients were divided into the AET - group (AET <4.2%) and AET+ group (AET >4.2%). GIP and PP levels were determined in all subjects and their associations with other parameters evaluated. Results: Age and GERDQ score were significantly higher (P<.05) and acid reflux and heartburn more frequent in the AET+ group than in the AET - group. The contraction front velocity was increased in the AET - group, while there was no significant difference in the distal contraction integral, peristalsis interruption, distal latency, or resting pressures of the lower and upper esophageal sphincters between the 2 groups (P>.05). The serum levels of GIP (P=.003) and PP (P=.012) were significantly increased in the AET + group. Increased GIP and PP levels were associated with abnormal upright AET (correlation coefficients 0.307 and 0.233, P=.008 and P=.047). There was a positive correlation between GIP and triglyceride levels (correlation coefficient 0.279, P=.017). Conclusion: The serum levels of GIP and PP in refractory GERD patients with prolongation of AET are significantly elevated, mainly in the upright position.