Conventional bismuth-based triple therapy has multiple problems, such as inadequate drug compliance, side effects, and drug resistance. Combination of omeprazole and clarithromycin with or without combination with antibiotics like amoxycillin has been shown to be effective in eradication of Helicobacter pylori. Reports from India are few on the efficacy of clarithromycin-based drug combinations. Therefore, we evaluated efficacy of omeprazole and clarithromycin with or without amoxycillin for treating H. pylori infection. Sixty-four consecutive patients with upper gastrointestinal symptoms and having H. pylori infection were included. In every patient, complete upper gastrointestinal endoscopy was done. H. pylori infection was diagnosed by identification of organism on antral biopsies and positive rapid urease test. Patients were treated with omeprazole 40 mg/day + clarithromycin 250 mg twice daily (group I, n = 22), or omeprazole 40 mg/day + clarithromycin 250 mg twice daily + amoxycillin 500 mg three times daily (group II, n = 20), or bismuth subcitrate 120 mg four times daily + amoxycillin 500 mg three times daily + metronidazole 400 mg three times daily (group III, n = 22) for 2 weeks. H. pylori status was reevaluated 1 month after completion of treatment. One patient in each group stopped drugs due to side effects. Eradication rate was not significantly different in group I (15/22, 68%), group II (14/20, 70%), and group III (13/22, 59%). Of those completing therapy, side effects were observed in three patients in group III (nausea, skin rash, metallic taste), whereas none of the patients in group I and group II had any side effects. Addition of amoxycillin did not appear to improve efficacy of dual omeprazole and clarithromycin therapy and appeared to be no different than bismuth, metronidazole, and amoxycillin triple therapy. Overall, none of regimens was particularly good.