Background/Aim: The effects of vonoprazan and proton pump inhibitors (PPIs) in patients with reflux esophagitis (RE) have not yet been compared using multichannel intraluminal impedance-pH (MII-pH). Methods: A total of 8 patients with persistent gastric mucosal injury, despite completing an 8-week standard PPI therapy, were enrolled in the study. While they were on standard PPI therapy, the baseline values of reflux parameters, holding time ratio (HTR) of gastric pH >4, and esophageal pH <4 were obtained by using 24 h MII-pH monitoring. They were re-evaluated after discontinuation of the therapy and 4 weeks of subsequent treatment with vonoprazan 20 mg/day. Results: The patients were found to be CYP2C19 extensive metabolizers and negative for Helicobacter pylori infection. In 7 patients (87.5%), the mucosal lesions had healed completely after vonoprazan therapy. A significant increase in gastric pH >4 HTR was observed, from 26.5 to 78.0% (p = 0.029). A reduction in esophageal pH <4 HTR was also observed but it was not statistically significant. Furthermore, acid clearance time and the total number of reflux events, including acid and proximal reflux events, were significantly reduced. Conclusion: Vonoprazan may be a better therapy for the treatment of patients with PPI-refractory RE.