OBJECTIVE Previous studies on the association between CYP2C19 polymorphisms and therapeutic outcome of clopidogrel in stroke patients are inconclusive. We aimed to investigate the impact of CYP2C19 polymorphisms on therapeutic efficacy of clopidogrel in both young and old minor stroke patients associated with large-artery atherosclerosis (LAA). METHODS A total of 510 eligible patients were enrolled between April 2015 and April 2018. During 1 year of follow-up, the modified Rankin Scale (mRS) was recorded. Statistical comparisons were performed using Pearson's chi squared test, Mann Whitney U test, and the Breslow-Day test to determine the effects of CYP2C19 polymorphisms on clinical outcome in different age strata. Multivariate binary logistic analysis was used to examine the potential prognostic predictors for clinical outcome. Model fitness was detected with Hosmer-Lemeshow test. RESULTS Sixty years old was identified as the optimal cutoff age for CYP2C19 polymorphisms to affect the clinical outcome of clopidogrel therapy in LAA-associated minor stroke patients (OR = 1.67; 95% CI 1.08-2.58). Comparisons of baseline characteristics between patients with favorable and poor outcome indicated the correlation between CYP2C19 loss-of-function (LOF) allele and poorer clinical outcome in ≤ 60-year-old patients (OR = 4.29; 95% CI 1.68-10.93). The heterogeneity test showed a presence of interaction between age and CYP2C19 LOF (OR = 3.75; 95% CI 1.30-10.81). The logistic analyses further suggested that CYP2C19 LOF predicted poor clinical outcome in ≤ 60-year-old but not in > 60-year-old LAA-associated minor stroke patients receiving clopidogrel for the second prevention. CONCLUSIONS Carriage of the CYP2C19 LOF allele may prevent expected clinical outcome during clopidogrel therapy in young LAA-associated minor stroke patients, whereas not in older patients.