Background: Helicobacter pylori (H. pylori) infection is prevalent in the world. Resistance to antibiotics is the main reason for treatment failure. This clinical trial examined the effect of clarithromycin versus levofloxacin as the content of first line of treatment of the patients with peptic ulcer.Methods: In this double-blind randomized controlled clinical trial study with parallel groups, 148 infected patients by H. pylori who had been proven during endoscopic biopsy were randomly divided into two equal groups. One group was treated with the quadruple therapy of clarithromycin 500 mg BID, amoxicillin 1 g BID, bismuth subcitrate 240 mg BID, and pantazole 40 mg BID. The second group was treated with levofloxacin 500 mg QD, amoxicillin 1 g BID, bismuth subcitrate 240 mg BID, and pantazole 40 mg BID. The duration of treatment was 14 days in both groups and four weeks after treatment, the eradication rate was assessed using the stool antigen test.Findings: The eradication rate was significantly higher using regime containing clarithromycin than that of levofloxacin [81.1%; confidence interval of 95% (95%CI): 72.2%-89.9% vs. 60.3%; 95%CI: 49.3%-72.2%; P = 0.021). The improvement in quality of life in patients treated with clarithromycin was comparable with levofloxacin (7.90 ± 5.79 vs. 9.27 ± 5.89; P = 0.18). Adverse effects were different between the groups in which bad taste was reported more frequently in clarithromycin than levofloxacin (27.0% vs. 4.3%) while epigastric pain was more in levofloxacin (7.1% vs. 2.7%).Conclusion: The effectiveness of clarithromycin on H. pylori eradication rate was significantly higher than levofloxacin.