Aim: To compare the efficacy of quadruple and sequential therapy in eradication of Helicobacter pylori (H. pylori) in a randomized study. Method: Three hundred H. pylori positive patients were enrolled into the study. These patients were randomly divided into two groups: group I (n = 150) received quadruple therapy (20 mg omeprazole bid, 240 mg bismuth subcitrate bid, 1,000 mg tetracycline bid and 500 mg metronidazole bid) for 14 days, group II (n = 150) received sequential therapy (20 mg omeprazole bid, 1,000 mg amoxicillin bid for 5 days, followed by 20 mg omeprazole bid, 500 mg metronidazole bid, 500 mg clarithromycin for the other 5 days). H. pylori status was assessed by histology and rapid urease test at baseline. Follow-up breath test by 14C urea breath test (UBT) was performed 4 weeks after completion of treatment. Eradication was defined as negative results on UBT. Results: Successful eradication was achieved in 245 patients. In each group, five patients did not tolerate the regimen and were excluded from analysis. About 29 (20%) patients who received sequential therapy and 21 (14.5%) of the quadruple group tolerated mild side effects (p = 0.21). Per-protocol analysis demonstrated eradication rates of 86.9% for sequential therapy and 82.7% for quadruple therapy (p = 0.26). Results according to the intention to treat analysis were 84 and 79.5% in the sequential and quadruple group respectively. Eradication rate differences were not significant. Conclusion: The success rate of sequential therapy is comparable with quadruple therapy. Sequential therapy due to the short duration and lesser drug usage is a good alternative for eradication of H. pylori in the country.