A combination of amoxycillin and omeprazole is often used to treat Helicobacter pylori infection. A three-drug regimen comprising metronidazole, amoxycillin and omeprazole has been proposed as an alternative therapy. In a prospective, randomized, comparative study, we evaluated these two regimens with respect to safety and efficacy in patients with H. pylori infection. Sixty patients with peptic ulcer (gastric, 32 patients; duodenal, 28 patients) who had a history of ulcer recurrence were randomly assigned to dual therapy with amoxycillin (500 mg three times daily for 2 weeks) and omeprazole (20 mg once daily for 8 weeks) or to triple therapy with metronidazole (500 mg twice daily for 2 weeks) plus amoxycillin and omeprazole, given in the same dosages as dual therapy. Forty-eight patients completed the protocol; treatment was discontinued because of side effects in nine patients, and three patients dropped out of the study. On the basis of all patients treated, the rate of H. pylori eradication was significantly higher for triple therapy 20/23 cases, 87.0%; 95% confidence interval (CI), 0.664-0.972) than for dual therapy 13/25, 52.0%; 0.313-0.722; P < 0.05). On an intention-to-treat basis, the difference between the groups in the rate of H. pylori eradication was marginally significant (P = 0.06 [0.028-0.512]). Side effects were reported by five patients receiving triple therapy (skin rash, one; nausea, two; headache, one; abdominal pain, one), and four patients receiving dual therapy (skin rash, two; abdominal pain, one; diarrhoea, one). All side effects resolved spontaneously after termination of treatment. There was no significant difference in safety between the two regimens. Triple therapy with metronidazole, amoxycillin, and omeprazole was significantly more effective for the eradication of H. pylori than dual therapy with amoxycillin and omeprazole alone. The safety of these regimens was similar, and triple therapy was found to be clinically acceptable.