Background: The most widely used treatments for ulcer healing and Helicobacter pylori eradication consist of a 1–2 week regimen of a proton pump inhibitor plus two or three antimicrobials. Aims: To evaluate the efficacy, safety, cost, and tolerance of a three‐day regimen with three antibiotics vs. a 10‐day treatment with a proton pump inhibitor or vs. a ranitidine bismuth citrate triple therapy. Methods: Two hundred and twenty‐one patients with endoscopically‐proven H. pylori‐positive duodenal ulcers were recruited to the study. Recruited patients were assigned to one of the following four regimens: (I) omeprazole 40 mg o.m. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (OAC: 55 patients); (ii) omeprazole 40 mg o.m. on days 1–5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3–5 (OACM: 56 patients); (iii) ranitidine bismuth citrate 400 mg b.d. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (RAC: 54 patients); (iv) ranitidine bismuth citrate 400 mg b.d. on days 1–5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3–5 (RACM: 56 patients). Fisher’s exact test was used to compare data regarding healing and eradication in the four groups. Results: The intention‐to‐treat eradication and ulcer healing rates for the RACM regimen were 95% and 98%, respectively. Statistically significant differences were observed, relating to the eradication and healing of ulcers, between RACM and either the RAC or OAC regimens. Conclusion: The three‐day antibiotic therapy with amoxycillin, clarithromycin and metronidazole in addition to ranitidine bismuth citrate is a very effective anti‐H. pylori regimen.