BACKGROUND AND AIMS: About 30% of patients with gastroesophageal reflux disease (GERD) are refractory to proton pump inhibitor (PPI). The reason for the PPI failure in Asian GERD patients has rarely been studied, and the therapy remained unclear. The aims were to explore the possible reasons for PPI failure and to treat these patients with the guidance of 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring. METHODS: Thirty-nine consecutive patients with refractory GERD were enrolled; 24-h MII-pH monitoring was performed on PPI. The refractory GERD patients were grouped into acid overexposure, non-acid reflux, and functional heartburn after the MII-pH monitoring. Double dose of either PPI or paroxetine was administered to refractory GERD patients within different groups. RESULTS: The number of patients in groups of acid overexposure, non-acid reflux, and functional heartburn was 6, 12, and 21, respectively. The acid overexposure group had the most acid reflux events. Among the acid overexposure group, five (5/6) patients accomplish symptom relief with double dose of esomeprazole. For the patients in non-acid reflux group, double dose of esomeprazole made half (6/12) of the patients obtain symptom relief. For the patients in functional heartburn group, the paroxetine had relieved the symptoms in 14 patients among all the 21 patients. In total, with the guidance of MII-pH monitoring, 64.1% (25/39) of refractory GERD patients accomplished symptom relief. CONCLUSIONS: Acid overexposure, non-acid reflux, and functional heartburn were the common reasons for persistent reflux symptoms despite PPI. With the guidance of MII-pH, a tailored therapy could resolve the persistent reflux symptoms among two-third of patients.