Vonoprazan is a novel acid blocker with greater potency than proton pump inhibitors. A Japanese study reported no significant safety concerns over 5 years of Vonoprazan use
however, elevated serum gastrin and increased parietal cell and foveolar hyperplasia were observed, and long-term safety data beyond 5 years are limited. We report a case that used Vonoprazan for 6 years, complicated by significant gastric epithelial changes during treatment and acute duodenal mucosal lesions following its discontinuation. A 76-year-old, treated with proton pump inhibitors for over 10 years, was switched to Vonoprazan due to his worsening symptoms. After its use, hemorrhagic hyperplastic polyps became prominent. Given concerns about Vonoprazan's effect on the gastric epithelium, the medication was changed to high-dose H2 blocker therapy. Two months later, the patient complained of vomiting and black tarry stools. Esophagogastroduodenoscopy revealed a significant reduction of gastric polyps but multiple erosions and ulcers in the duodenum. This case indicates the potent effects of Vonoprazan on the gastric mucosa and the risk of severe rebound acid hypersecretion after its long-term use.