Background: Treatment of Helicobacter pylori (H.pylori) became mandatory for prevention and cure of most upper gastrointestinal complaints. Despite the varieties in available therapeutic options, achieving a high eradication rate is very challenging. Currently, vonoprazan based protocols are being introduced, and they provide promising outcomes. We aimed at studying vonoprazan efficacy and safety for cure of H.pylori among Egyptian patients. Methods: In a prospective cohort study, we included 300 patients who tested positive for H. pylori to receive vonoprazan-based triple therapy for two weeks. Then, we assessed the cure rate, improvement of symptoms and side effects. Results: We found that vonoprazan-based triple therapy achieved a cure rate of 90%. There was a remarkable improvement in all presenting symptoms after complete cure with this regimen. Few adverse effects were observed, not exceeding 9.3% of patients. Most common side effects were nausea (4.3%), burping (2.6%) and bloating (1.3%). Conclusions: vonoprazan-based triple therapy is effective and safe for cure of Helicobacter.