BACKGROUND: Antibiotic treatment selects for resistance not only in the pathogen to which it is directed but also in the indigenous microflora. OBJECTIVE: To determine whether a widely used regimen (clarithromycin, metronidazole, and omeprazole) for Helicobacter pylori eradication affects resistance development in enterococci. DESIGN: Cohort study. SETTING: Endoscopy units at 3 community hospitals in Sweden. PATIENTS: 5 consecutive dyspeptic patients who were colonized with H. pylori, had endoscopy-confirmed duodenal ulcer, and received antibiotic treatment, and 5 consecutive controls with dyspepsia but no ulcer who did not receive treatment. MEASUREMENTS: Fecal samples were obtained from patients and controls before, immediately after, 1 year after, and 3 years after treatment. From each patient and sample, enterococci were isolated and analyzed for DNA fingerprint, clarithromycin susceptibility, and presence of the erm(B) gene. RESULTS: In treated patients, all enterococci isolated immediately after treatment showed high-level clarithromycin resistance due to erm(B). In 3 patients, resistant enterococci persisted for 1 to 3 years after treatment. No resistance developed among controls. CONCLUSION: A common H. pylori treatment selects for highly resistant enterococci that can persist for at least 3 years without further selection.