Up-to-datedata about the role of acid suppression therapy e.g. proton-pump inhibitors; to reduce post-endoscopic variceal ligation (EVL) ulcer-bleeding are conflicting. Vonoprazan; a recently introduced potassium-competitor acid blocker, has not been studied to prevent post-EVL ulcer/bleeding. The aim was to evaluate the efficacy of vonoprazan vs. pantoprazole or non-acid suppression to prevent post-EVL ulcer/bleeding in portal hypertension patients. We enrolled 275 portal hypertension patients undergoing EVL in a three-arm randomized, single-blind, controlled study. A clinico-laboratory baseline evaluation was performed. Following EVL, patients were randomly and equally assigned to receive vonoprazan 20mg once daily, pantoprazole 40mg once daily, or no acid suppression therapy. Post-EVL ulcer bleeding, ulcer dimensions, odynophagia as well as vonoprazan safety were evaluated after 2 weeks of EVL. Post-EVL ulcer bleeding occurred among 2.15% of vonoprazan, 8.7% of pantoprazole, and 14.2% of the non-acid suppression groups (P<0.001). Post-ligation ulcer frequency and dimensions were higher among non-acid suppression and pantoprazole groups vs. vonoprazan (P<0.05). Chest pain and odynophagia were encountered among 73.6% and 54.9% of the non-acid suppression group vs. 39.6% and 45.1% in pantoprazole, and 17.2% and 21.5% in vonoprazan groups, respectively (P<0.05). There were no vonoprazan-related adverse events. Non-use of vonoprazan was the strongest independent predictor for post-EVL bleeding. Short course of vonoprazan 20mg/day is safe and superior to pantoprazole 40mg/day in the reduction of post-EVL ulcer dimensions at 2 weeks post-EVL, and prevention of ulcer-related bleeding. Acid suppression is superior to no acid suppression to prevent post-EVL complications.