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Introduction Patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI) receive clopidogrel and direct oral anticoagulation. Platelet inhibition by clopidogrel varies according to CYP2C19 genotype. This study aimed to investigate the association of CYP2C19 genotype with antiplatelet effect of clopidogrel and ischemic and bleeding risk. Methods In this prospective observational study, patients with AF after PCI were grouped according to CYP2C19*2 and *17 diplotypes: *2/non-17* or *2/*2 as reduced metabolizers (RM), non-*2/*17 or *17/*17 as increased metabolizers (IM), and the remaining as normal metabolizers (NM). Platelet aggregation [U] was quantified by multiple electrode aggregometry. The primary outcome was time to death, myocardial infarction, or stroke (MACE) at 6 months. The secondary outcome was time to non-major clinically relevant (NMCR) or major bleedings. Results 156 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 71–82) and 109 (70%) were male. 31 patients (20%) were RM, 74 patients (47%) NM and 51 patients (33%) IM. The median ADP-induced platelet aggregation was not significantly different across these groups (RM: 12.8 [U]; NM: vs. 12.8 [U]; IM: 11.7 [U]; P = 0.39).The primary outcome occurred in 11 (7%) patients (RM: 1 [3%]; NM: 7 [9%]; IM 3[6%]). The secondary outcome occured in 3 RM (10%) and in 20 (16%) with NM + IM subtypes (HR 0.65 [95% CI 0.19–2.18], P = 0.485). Conclusion In this analysis reduced metabolizers were not at excessively increased risk of MACE. A trend for less bleeding was observed in carriers of loss-of-function allele CYP2C19*2.