Helicobacter pylori represents the major cause of gastric cancer, gastric lymphoma and peptic ulcer diseases. In some cases, the infection persists even after three rounds of treatment. The evaluated article reports on the efficacy of an empirical multicenter, prospective fourth‑line rescue study with rifabutin in patients with three consecutive eradication failures. A total of 100 patients (31% peptic ulcer and 69% functional dyspepsia) were included to receive a fourth‑line with rifabutin (150 mg twice daily [b.i.d.]), amoxicillin (1 g b.i.d.) and a proton‑pump inhibitor (standard dose b.i.d.) for 10 days. The end point was H. pylori eradication, determined by (13)C-urea breath test 4-8 weeks after therapy. H. pylori eradication was achieved in approximately 50% of patients. Adverse events (mainly metallic taste, nausea and diarrhea) were reported in 30 patients. Thus, a fourth-line rifabutin-based rescue therapy constitutes a valid strategy after multiple previous H. pylori eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin.