Context Antimicrobial resistance has decreased eradication rates for Helicobacter pylori (H. pylori) infection worldwide. Sequential therapy (ST) has been suggested as an alternative to conventional triple therapy (TT) for the first-line treatment of H. pylori. Aim The purpose of this study was to compare the efficacy and tolerance of levofloxacinbased ST with clarithromycin-based TT. Materials and methods This is a randomized open-label clinical trial carried out on 134 patients with dyspepsia selected from Outpatient Clinic of Hepatology and Gastroenterology Department, Zagazig University Hospital, from October 2015 till September 2016. All patients were H. pylori positive as evidenced by C13-urea breath test and rapid urease test. Patients were divided into two groups: group I 67 patients received levofloxacin-based ST whereas group II 67 patients received clarithromycin-based TT for 14 days. Eradication rates, drug compliance, and adverse events were compared among the two regimens. Results The intention-to-treat eradication rates were 71.6% for TT and 91% for ST (P=0.004). The adverse effects including nausea, vomiting, abdominal pain, and diarrhea were less in levofloxacin-based ST than clarithromycin-based TT, but there was no statistically significant difference (all P>0.05). Conclusion Theefficacyoflevofloxacin-basedSTissignificantlybetterinthetreatmentofH.pylori than TT, and it also shows good tolerability. Countries like Egypt seem to have a high clarithromycin resistance, and a large-scale clinical trial is needed to choose the firstline therapy for eradication of H. pylori infection.