H. pylori infection is common worldwide involving 50% of the general population. The aim of this study was to compare the effect of two sequential regimen therapies on the eradication of H. pylori. In this clinical trial, 150 patients were allocated to two groups of 75 each: group A and group B. The eradication of H. pylori in groups A and B was based on azithromycin and ofloxacin sequential regimens, respectively, and the results were compared between the groups. The data were analyzed by t-test, Chi-square test, and Fisher’s exact test using SPSS software version 16. Mean of the patients’ age was 39.3±1.2 within the age range of 18 to 85 years. There were not significant differences between the two groups considering the type of peptic ulcer. In group A, Urea Breath Test (UBT) was negative in 67 (89.3%) patients while in group B, it was only positive in 8 (10.7%) patients. In group B, there were 64 (85.3%) negative and 11 (14.7%) positive UBT test results. There were no significant differences in H. pylori eradication rates between the two groups (P= 0.31). Noticing the absence of a significant difference between the two groups in terms of H. pylori eradication, it can be concluded that ofloxacin-based drug regimens have no superiority over azithromycine-based regimens and each regimen can be prescribed considering drug complication rates in different patients.