Background: Antibiotic resistance has increasingly been recognized as the major cause of treatment failure for Helicobacter pylori infection. New therapies for patients with metronidazole‐ or clarithromycin‐resistant H. pylori are needed. Aim: To investigate the role of nitrofurantoin quadruple therapy for the treatment of H. pylori. Methods: Patients with confirmed H. pylori infection received nitrofurantoin (100 mg t.d.s.), omeprazole (20 mg b.d.), Pepto‐Bismol (two tablets t.d.s.), and tetracycline (500 mg t.d.s.) for 14 days. Four or more weeks after the end of therapy, outcome was assessed by repeat endoscopy with histology and culture or urea breath testing. Results: Thirty patients were entered, including 25 men and five women; the mean age was 54.9 years. The most common diagnoses were duodenal ulcer (23%) and GERD (18%). The intention‐to‐treat cure rate was 70% (95% CI: 50.6–85%). Nitrofurantoin quadruple therapy was more effective with metronidazole‐sensitive strains (88%; 15 out of 17) than with metronidazole‐resistant strains (33%; three out of nine; P=0.008). Two of the treatment failures had pre‐treatment isolates susceptible to metronidazole, which were resistant after therapy. Conclusions: Because nitrofurantoin quadruple therapy performed inadequately in the presence of metronidazole resistance, we conclude that nitrofurantoin is unlikely to find clinical utility for the eradication of H. pylori.