Abstract Background The success rate of conventional Helicobacter pylori eradication therapy is declining, due to rising antibiotic resistance. Objectives To determine the temporal effects of prior antibiotic exposure on eradication outcome. Patients and methods This is a retrospective cohort study including all H. pylori-infected patients who received their first course of clarithromycin-containing triple therapy in 2003–18. Prior antibiotic exposures before H. pylori eradication therapy (up to 180 days, 1 year or 3 years) were retrieved. A logistic regression model was used to evaluate the association between different timings of previous antibiotic exposure, recent (within 30/60 days) or distant period, and the need for retreatment for H. pylori. Results A total of 120 787 H. pylori-infected patients were included. Prior exposure to any antibiotics within 180 days was associated with a higher risk of retreatment (OR 1.18, 95% CI 1.13–1.24) and the risk progressively increased with longer duration of antibiotic use. The results were consistent for prior exposure up to 1 year (OR 1.26, 95% CI 1.20–1.31) or 3 years (OR 1.30, 95% CI 1.25–1.35). However, when compared with those without prior antibiotic exposure, recent exposure (within 30 days) did not increase the risk of retreatment, which was consistent for analysis with prior antibiotic exposure up to 3 years. Notably, recent use of cephalosporins within 30/60 days and nitroimidazole within 30 days had significantly lower risks of retreatment. Conclusions Any prior antibiotic exposure increased the risk of treatment failure of clarithromycin-containing triple therapy. Recent exposures to some classes of antibiotics may paradoxically increase treatment success.