BACKGROUND The prevalence of Helicobacter pylori (H. pylori) in developing countries is 50.8%, with the highest occurrence presented in Africa (79.1%). It increases the risk of chronic gastritis, peptic ulcer, cancer of the stomach, and lymphoma. The effect of standard treatment for H. pylori eradication is below 80%, and evaluation of alternative lines of treatment is needed. We aimed to compare the hybrid, reverse hybrid, and levofloxacin quadruple therapies as first-line therapy in Egypt. METHODS This was a randomized interventional trial done in the clinics affiliated with the Internal Medicine Department. 330 individuals were selected according to the inclusion criteria. They were divided into three groups: group 1 (110 subjects who received a reverse hybrid regimen), group 2 (110 subjects who received a hybrid regimen), and group 3 (110 subjects who received a non-bismuth levofloxacin quadruple regimen). RESULTS Group 3 had a significantly lower eradication rate of 82.7% versus 92.7% and 91.8% in groups 1 and 2, respectively. There were non-significant differences in the incidence rates of adverse events among the three groups. CONCLUSION Both the reverse hybrid and hybrid groups had good eradication rates in the Egyptian population, but non-bismuth levofloxacin quadruple therapy did not obtain a sufficient eradication rate.