Aims Clopidogrel is used as secondary prevention after cerebral ischaemia. Previous, mainly Asian, studies have shown that genetic variations in CYP2C19 are associated with an increased risk of recurrent stroke in clopidogrel‐treated patients. Evidence on the impact of this drug–gene interaction in European neurology patients is currently limited. The aim of this study is to compare the prevalence of CYP2C19 loss‐of‐function (LoF) alleles in a population with recurrent cerebral ischaemia to two reference groups from the same region. Methods CYP2C19‐genotyping (*2 and *3) was performed in clopidogrel‐treated patients who presented with a recurrent ischaemic stroke/transient ischaemic attack (TIA). Genotype distributions were compared with two reference groups; a cohort of consecutive patients who underwent elective coronary stent implantation and a cohort of healthy Dutch volunteers. Results In total, 188 cases with a recurrent ischaemic event were identified, of whom 38 (20.2%) experienced an early recurrent event (24 hours to 90 days after the previous event). Among the total case group, 43.6% of the patients carried at least one CYP2C19 LoF allele, compared with 27.6% and 24.7% in respectively the cardiology and the healthy volunteers reference groups (P < .001 for both comparisons). Among the cases with an early recurrent event, 55.3% of patients were carriers of at least one CYP2C19 LoF allele (P < .0001). Conclusion In this clopidogrel‐treated population with recurrent cerebral ischaemia, the frequency of CYP2C19 LoF alleles was significantly higher than in reference groups, especially in early recurrent events. This study adds to the growing body of evidence that genotype‐guided antiplatelet therapy could improve patient outcomes.

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