BACKGROUND: Helicobacter pylori eradication by the conventional clarithromycin therapy has largely dropped in the recent years possibly due to antimicrobial resistance. Hence, levofloxacin-based regimen has been used as salvage therapy. However, data regarding its effectiveness on eradication are controversial. This study aimed to compare the eradication rate of levofloxacin-based regiment to that of the conventional first-line clarithromycin regimen. METHODS: Patients diagnosed with H. pylori infection and treated with levofloxacin triple therapy or clarithromycin-based regimen for 10 or 14 days were included. Patients were excluded if they used antibiotics or proton pump inhibitors within 4 or 2 weeks, respectively, of the H. pylori eradication confirmation test. H. pylori eradication rate was assessed, as well as the impact of diabetes and esophagogastroduodenoscopy (EGD) findings. RESULTS: Of 245 patients, 145 were in the levofloxacin group and 100 in the clarithromycin group. Most patients in either group received therapy for 14 days vs. 10 days (P = 0.002). Levofloxacin-based treatment was associated with a higher eradication rate compared with clarithromycin-based treatment (74.5 vs. 62%, respectively; P = 0.04). The 14 day levofloxacin-based regimen resulted in the highest eradication rate, followed by the 14 day regimen of clarithromycin (80.9 vs. 66.3%; P = 0.03). The 10 day regimens exhibited 62.7 and 41.2% eradication rates, respectively (P = 0.12). H. pylori eradication was not affected by diabetes or EGD findings (P = 0.98 and 0.3, respectively). CONCLUSIONS: Results from this study support the use of a levofloxacin-based regimen as a first-line therapy in the treatment of H. pylori infection for 14 days regardless of diabetes and EGD findings.