Background and study aim: Absence of adequate treatment for Helicobacter pylori (H. pylori) infection leads to prolonged life time colonization which is responsible for complications. Antibiotics resistance is the main cause of eradication failure in H. pylori infection, thus our study aimed to evaluate the efficiency and tolerability of standard triple therapy vs. quadruple regimen therapy in H. pylori eradication in Egypt. Subjects and Methods: Our study enrolled 140 patients (65 males,75 females) who attending to Gastroenterology clinic in Internal medicine & Tropical medicine departments, Zagazig University Hospitals from (June 2018 - June 2019), aged from 20 - 60 years, complained of recurrent non-specific dyspepsia and epigastric pain & proved to be positive for H. pylori stool antigen test. The patients distributed into two groups: group (1), 70 patients given Clarithromycin triple therapy [Clarithromycin 500 mg + Amoxicillin 1gm + Pantoprazole 40 mg, each twice daily]. Group (2), 70 patients given quadruple therapy [Levofloxacin 500 mg once daily + Nitazoxanide 500mg (twice daily)+ Doxycycline 100 mg (twice daily)+ Pantoprazole 40 mg (twice daily)] for 14 days. Results: H. pylori eradication rate was statistically significant higher in patients who received quadruple therapy compared to those who received Clarithromycin-based triple therapy ( 85.7% vs. 67.1 % & P = 0.001 respectively).While, statistically insignificant regarding the treatment side effects in both groups ( 11.4 % vs. 14.3 %, P= 0.33 respectively). Conclusion: Quadruple therapy is preferable to Clarithromycin-contained triple therapy in tolerability and eradication of H. pylori in Egypt.