Background: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. Objectives: To test the effectiveness of susceptibility guided therapy vs. the empirical triple therapy for first: line H pylori treatment in a region with high antimicrobial resistance. Patients and methods: The study was performed on 82 dyspeptic H. pylori patients arranged for esophagogastroduodenoscopy at Al-Hussein University Hospital between March 2019 to march 2020. Patients were randomly divided into two groups: group A consisted of 52 patients underwent endoscopy and gastric biopsies for culture and sensitivity and treated according to sensitivity results and group B consisted of 30 patients treated by empiric triple therapy. Eradication rates and drug compliance owing to adverse effects were compared between the two groups. Results: In total, 82 patients were enrolled (52 in culture and sensitivity-based therapy group and 30 in empirical therapy group) and 50 patients (60.1%) completed the protocols. The overall resistance rates to clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, nitrofurantoin and rifampicin were 32.1%, 32.1%, 78.6%, 7.1%, 17.9%, 17.9% and 21.4% respectively. Empirical triple and antimicrobial susceptibility-guided eradication rates were, respectively, 53.3% and 85.7% by intention-to-treat and 64% and 96% by per-protocol analysis. Adverse events were reported in 16.6% of patients on empirical triple therapy and 21.4% of those on susceptibility-guided therapy. Conclusions: Culture-based eradication strategy demonstrated superior eradication efficacy than empirical therapy as a first-line therapy in a region with high levels of antimicrobial resistance.