BACKGROUND: A proportion of patients with functional dyspepsia (FD) have inadequate symptom control with proton pump inhibitors (PPIs) treatment. Vonoprazan demonstrates higher efficacy in acid reduction than PPI; however, the existing efficacy data for vonoprazan in treating PPI-refractory FD is limited. METHODS: This double-blinded, randomized controlled trial study was conducted at Rajavithi Hospital, Bangkok between December 2022 and 2023. Patients with FD who were unresponsive to the standard dose PPI were randomly assigned (1:1) to receive either 10 mg or 20 mg of vonoprazan for a 4-week duration, with a subsequent 4-week follow-up after treatment. The primary outcome was changes in the Global Overall Symptoms Scale (GOSS). RESULTS: Sixty patients were randomized without significant differences in baseline characteristics between both groups. The mean GOSS between the 10-mg vonoprazan and the 20-mg vonoprazan arm were 25.73 and 26.17 at week 0, 14.33 and 15.50 at week 2, 9.37 and 10.04 at week 4, and 9.79 and 9.33 at week 8, respectively (all  < 0.001 vs. baseline and  > 0.05 between groups). The quality of life was improved, with the Nepean dyspepsia index changing -4.13 and -4.25 at week 4, respectively (all  < 0.001 vs. baseline;  = 0.853 between groups). Symptom response rates (> 50% improvement in GOSS) were 72.4% and 75.9% at week 8, respectively ( = 0.24 between groups). No serious adverse events were observed. CONCLUSION: Vonoprazan demonstrated significant effects in the alleviation of symptoms in PPI-refractory FD patients. There was no statistically significant difference in symptom alleviation between the 10 mg and 20 mg doses of vonoprazan.