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Background CYP2C19 genotyping has been widely studied to guide antiplatelet therapy in cardiovascular disease; however, its role in neurointerventional procedures, particularly for unruptured intracranial aneurysms (UIA), remains underexplored. This study aimed to evaluate the clinical utility of CYP2C19-guided antiplatelet therapy following stent-assisted coil embolization (SAC) in patients with UIA.Methods A total of 403 patients who underwent SAC were included. The control group (n=220) received standard dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, without genotyping. The genotype-guided group (n=183) received personalized DAPT based on the CYP2C19 metabolizer status. The primary outcome was the occurrence of intracranial ischemic events within 90 days of surgery. The secondary outcomes included systemic hemorrhagic events.Results Intracranial ischemic events occurred in 33 patients: 24 (10.9%) in the control group and 9 (4.9%) in the genotype-guided group, representing a relative risk reduction of 54.9% (P=0.029). Systemic hemorrhagic events were reported in 22 patients: 10 (4.5%) in the control group and 12 (6.6%) in the genotype-guided group, with no statistically significant difference (P=0.388).Conclusion CYP2C19-guided antiplatelet therapy significantly reduces the risk of intracranial ischemic events after SAC in patients with UIA without increasing systemic bleeding complications. This genotype-based approach may enhance the safety and efficacy of perioperative management of neurointerventions.