OBJECTIVE The study aims were to evaluate and compare the effectiveness and safety of non-bismuth quadruple therapy with sequential therapy and dual therapy with high dose esomeprazole and amoxicillin as an empirical first-line approach to eradicate Helicobacter pylori infection. METHODS Prospective randomized trial included 393 patients infected with H. pylori naïve to eradication therapy, randomized to receive a 10-day non-bismuth quadruple or concomitant (CT) therapy, 10-day sequential therapy (SQ), or 14-day high-dose esomeprazole and amoxicillin (BT). Treatment outcome was assessed by C13-urea breath test at least six weeks after therapy. Adverse events and compliance were assessed with questionnaires and residual medication count. RESULTS The baseline demographic clinical and endoscopic characteristics were similar among the three groups. The intention to treat (ITT) analysis was performed in 130, 132, and 131 patients in the BT, SQ, and CT groups, respectively. The eradication rates in ITT were 64.6%, 83.1%, and 92.3%, respectively, in the BT, SQ and CT groups (p = 0.0001). The eradication rates per protocol were 67.7%, 88.5%, and 95.3% (p = 0.0001), respectively, in the BT, SQ, and CT groups. The CT and SQ groups were higher than the BT group (p = 0,0001) but no significant results were seen in the eradication rate between CT and SQ, both in PP analysis and in ITT analysis (p = 0.09). The prevalence of the side effects following the non-bismuth quadruple therapy was 38.2%, significantly higher (p = 0.001) than the BT group (13.80%) and SQ group (22%). There were no significant differences in compliance among the three therapies (p = 0.16). CONCLUSIONS This study found that non-bismuth quadruple therapy yielded a higher H. pylori eradication rate over sequential regimen as a first-line treatment in Morocco, with no statistical difference between the two protocols studied, while the eradication rate of dual high-dose of esomeprazole and amoxicillin did not exceed 60%. All three therapy schemes showed excellent compliance. However, the prevalence of side events was more important and significantly higher with non-bismuth quadruple therapy.