BACKGROUND Helicobacter pylori (H. pylori) infection is a major casual factor in any peptic diseases. Clarithromycin as one of the drugs recommended for the infection eradication regimen has shown different levels of resistance. The present study is comparing the effectiveness of clarithromycin- and gemifloxacin - based quadruple regimens in H. pylori eradication. METHODS This was a prospective double blind randomized clinical trial on patients with clear indication of H. pylori eradication. The patients were randomly divided into two groups: "BPAC group" treated with bismuth subcitrate (240 mg), pantoprazole (20 mg), amoxicillin (1 gr), and clarithromycin (500 mg), all twice daily, and the "BPAG group" treated with bismuth subcitrate, pantoprazole, and amoxicillin with same doses as "BPAC group" and gemifloxacin (320 mg daily) all for 10 days. Three months after the end of therapy, 14C-Urea breath test was performed to confirm the eradication. All the patients were assessed for compliance and drug side effects. Based on per-protocol (PP) and intention-to-treat (ITT) methods, data were analyzed and a P value<0.05 was considered as statistically significant. This project has been registered in the Iranian registry of clinical trials (IRCT). RESULTS Three patients were excluded from the survey and finally, 179 patients (89 patients in BPAC group and 90 patients in BPAG group) including 71(39.66%) men with the mean age of 46.4±12.3 years completed the treatment period. The incidence of side effects between the two study groups did not differ significantly. The success rate of BPAC regimen eradication was remarkably greater than BPAG regimen (ITT analysis; 89% vs 77%, respectively; CI 95%: 1.072-5.507, P<0.015 and PP analysis; 91% vs 77.8% respectively; CI 95%: P<0.015). There was no significant relationship between the demographic features and the eradication results. CONCLUSION The results showed that gemifloxacin is not a good alternative for clarithromycin in H. pylori eradication regimens in our region.