BACKGROUND AND AIM: Both clarithromycin-resistant Helicobacter pylori and CYP2C19 polymorphisms may be passed down for generations and are known risk factors for the failure of H. pylori eradication therapy. However, no study has evaluated the risk of clarithromycin triple therapy failure in patients with a parental history of such failure. This study investigated the association between a history of clarithromycin triple therapy failure in parents and clarithromycin triple therapy failure in the offspring. METHODS: This cross-sectional study was conducted using a large administrative claims database of 3 100 000 insured individuals. We identified 404 patients who had both personal and parental records of prescriptions for first-line clarithromycin triple therapy between January 2005 and February 2018. Failure of clarithromycin triple therapy was defined as treatment with second-line therapy after having received first-line clarithromycin triple therapy. A parental history of clarithromycin triple therapy failure was defined as failure of clarithromycin triple therapy by either the father or the mother. Odds ratios were estimated using logistic regression models adjusted for age, sex, diabetes mellitus, and peptic ulcer. RESULTS: The incidence of clarithromycin triple therapy failure was 22.5% (91/404). Based on univariate analysis (odds ratio [95% confidence interval], 1.90 [1.10-3.29]) and multivariable analysis (odds ratio [95% confidence interval], 1.93 [1.10-3.39]), parental history of clarithromycin triple therapy failure was associated with failure of clarithromycin triple therapy in the offspring. CONCLUSION: A parental history of clarithromycin triple therapy failure is a risk factor for failure of clarithromycin triple therapy in the offspring.