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Background Helicobacter pylori eradication is a key strategy for preventing peptic ulcer disease and gastric cancer, and current consensus recommends eradication therapy for all infected individuals. However, implementing large-scale eradication would increase population-level antibiotic exposure, raising concerns regarding antimicrobial resistance (AMR). While prior resistance surveillance focused primarily on H. pylori isolates and eradication efficacy, the long-term clinical consequences of eradication therapy on AMR and downstream infections at the population level remain poorly characterized.Methods In this multinational retrospective cohort study, patients diagnosed with peptic ulcer diseases or gastritis who received proton pump inhibitors (PPIs) within 6 months were included and followed up for 10 years. Those receiving H. pylori eradication therapy of any regimen were compared with PPI-only controls. Propensity score matching controlled for demographics, prior infection or AMR events, gastrointestinal diseases, concomitant medications, and comorbidities. The primary outcome was incident AMR events, including class-specific and multidrug resistance. Secondary outcomes included infection-related events, prespecified negative control outcomes, and all-cause mortality. Subgroups were stratified by sex, age, and eradication regimen.Results After matching, 24,660 patient pairs were included. During the 10-year follow-up, H. pylori eradication was associated with a sustained increase in incident AMR events compared to matched controls (IDDF2026-ABS-0446 Figure 1. Cumulative incidence of antimicrobial resistance (AMR) events of patients receiving H. pylori eradication or PPI only within 10 years), corresponding to a hazard ratio (HR) of 1.52 (95% confidence interval [CI], 1.39-1.66) with risk peaking within the first two years (IDDF2026-ABS-0446 Figure 2. Association between H. pylori eradication and 10-year risk of (A) AMR and (B) infection-related outcomes in patients with peptic ulcers or gastritis, IDDF2026-ABS-0446 Figure 3. The risk of overall AMR and class-specific resistance in patients receiving H. pylori eradication at different timepoints compared to patients with PPIs only). The number needed to have for one additional AMR event is 51. The risks of gastrointestinal infections, Clostridioides difficile infection, sepsis, and mortality were also significantly increased (IDDF2026-ABS-0446 Figure 2. Association between H. pylori eradication and 10-year risk of (A) AMR and (B) infection-related outcomes in patients with peptic ulcers or gastritis). Risk stratification revealed the greatest AMR risk among patients younger than 25 and in those receiving quinolone-based (TT-Q) or metronidazole-based (TT-M) triple therapies (IDDF2026-ABS-0446 Figure 4. The risk of overall AMR in patients receiving H. pylori eradication stratified by age, sex, and eradication regimen).Conclusions In this large, long-term, population-based cohort, we demonstrated that H. pylori eradication is associated with sustained long-term risks of AMR and infection-related adverse outcomes, with excess risk in younger individuals and those treated with TT-Q and TT-M regimens. These results highlight the need to balance cancer-prevention benefits with downstream resistance risks in H. pylori eradication.Abstract IDDF2026-ABS-0446 Figure 1Abstract IDDF2026-ABS-0446 Figure 2Abstract IDDF2026-ABS-0446 Figure 3Abstract IDDF2026-ABS-0446 Figure 4