BACKGROUND: Several 'rescue' therapies have been recommended to eradicate Helicobacter pylori, but they still fail in >20% of the cases, and these patients constitute a therapeutic dilemma. AIM: To evaluate the efficacy of different 'rescue' therapies empirically prescribed during 10 years to 500 patients in whom at least one eradication regimen had failed to cure H. pylori infection. DESIGN: Prospective single-centre study. PATIENTS: Consecutive patients in whom at least one eradication regimen had failed. INTERVENTION: Rescue regimens included: (i) quadruple therapy with omeprazole-bismuth-tetracycline-metronidazole; (ii) ranitidine bismuth citrate-tetracycline-metronidazole; (iii) omeprazole-amoxicillin-levofloxacin; and (iv) omeprazole-amoxicillin-rifabutin. Antibiotic susceptibility was unknown (rescue regimens were chosen empirically). OUTCOME: Eradication was defined as a negative (13)C-urea breath test 4-8 weeks after completing therapy. RESULTS: Five hundred patients were included (76% functional dyspepsia, 24% peptic ulcer). Compliance rates with first-, second- and third-line regimens were 92%, 92%, and 95%, respectively. Adverse effects were reported by 30%, 37%, and 55% of the patients receiving second-, third-, and fourth-line regimens. Overall, H. pylori cure rates with the second-, third-, and fourth-line rescue regimens were 70%, 74%, and 76%, respectively. Cumulative H. pylori eradication rate with four successive treatments was 99.5%. CONCLUSION: It is possible to construct an overall treatment strategy to maximize H. pylori eradication, on the basis of administration of four consecutive empirical regimens; thus, performing bacterial culture even after a second or third eradication failure may not be necessary.