Article informationBackground: The most commonly known abnormality of gastric acidity is gastroesophageal reflux disease [GERD] which is treated by proton pump inhibitors [PPIs]. One of the new family of gastric acid-suppressing medications is vonoprazan that works as a potassium-competitive acid blocker [P-CABs]. Aim of the Work:To compare the effectiveness of 20 mg vonoprazan versus omeprazole 40 mg once daily half an hour before breakfast as a treatment of symptoms and mucosal healing in GERD patients.Patients and Methods: Sixty cases, proven to have GERD, were enrolled in a comparative clinical trial after having upper endoscopes. Cases were classified into two groups, 30 patients each; group [A] received omeprazole 40 mg once daily, whereas group [B] received vonoprazan 20 mg once daily for 8 weeks, then reevaluation of both groups by symptoms relief using GERD Q score, frequency scale of the symptoms of gastroesophageal reflux disease questionnaire [FSSG] and upper endoscopy was done for all patients after 8 weeks. For each patient, medical history taking, clinical examination, routine laboratory investigations, and upper endoscopy with GERD classification according to LA classification were done.Results: No detected differences between the included groups regarding GERD Q Score and FSSG score. Our data showed that complete symptoms resolution was somewhat higher among the omeprazole group compared to the vonoprazan group without a statistically significant difference. There is a significant decrease in reflux score, and total score in both groups however, the drop in FSSG scores was more significant in group A in comparison to group B. Conclusion:Vonoprazan showed no superiority over omeprazole in relief of typical symptoms and mucosal healing in patients with GERD; the drop in FSSG scores was more significant in omeprazole group compared to vonoprazan group.