Background: Helicobacter pylori (H.pylori) infection causes multiple upper gastrointestinal diseases but optimal therapeutic regimen which can eradicate infection in all the cases has not yet been defined. Antimicrobial resistance has decreased eradication rates for H.pylori infection worldwide. The aim of the present study was to compare between the efficacy and tolerability of levofloxacin versus Clarithromycin based triple therapy in eradication of H.pylori infection. Subjects and Methods: In this comparative cross sectional study, 142 patients with epigastric pain and dyspepsia and positive stool antigen test and only 35 of them were further confirmed by Rapid Urease Test during upper endoscopy (endoscopy was indicated) were enrolled. They were divided into 2 groups The first group (levofloxacin group) was treated with levofloxacin (500 mg daily) plus amoxicillin (1 gm twice a day) plus pantoprazol (40 mg twice daily) for 2 weeks. The second group (clarithromycin group) was treated with clarithromycin (500 mg twice a day) plus pantoprazol (40 mg twice daily) plus amoxicillin (1 gm twice a day) for 2 weeks. For treatment evaluation Stool antigen test was performed after four weeks after cessation of therapy. Results: H.pylori eradication was successful in 84.5% of the levofloxacin group and 69% of the clarithromycin group (P=0.001). The adverse effects were less frequent in levofloxacin-based than clarithromycin-based Ttiple therapy. Conclusion: Triple therapy with levofloxacin-based regimen has better efficacy than clarithromycin-based regimen.