Introduction Dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine (eg, clopidogrel) prevents stent related thromboembolic events in cardiac patients and is frequently utilized during neurointerventional surgery. However, recent data suggest that many patients exhibit clopidogrel resistance. Prasugrel - a newer thienopyridine - lowers the rate of cardiac stent thromboses in clopidogrel non-responders but a paucity of data exist regarding its safety and efficacy in neurointerventional surgery. Methods All patients undergoing neurointerventional surgery by a single interventionalist (CJM) over a 20 month period were retrospectively identified. Charts were reviewed for pre- and post-procedural DAPT regimens, pre-procedural coagulation parameters and procedural complications. Results 76 patients received pre- and post-procedural DAPT for endovascular treatment of an intracerebral aneurysm, dural arteriovenous fistula or intra/extracranial arterial stenosis. 51 patients underwent 55 total procedures and were treated with aspirin/clopidogrel; 25 patients underwent 31 total procedures and were treated with aspirin/prasugrel. Those patients who received aspirin/prasugrel DAPT were identified preprocedurally to be clopidogrel non-responders. Both treatment groups had a similar percentage of patients undergoing aneurysm coiling, stent assisted aneurysm coiling, aneurysm Onyx embolization, aneurysm pipeline embolization device treatment, extra/intracranial carotid artery angioplasty and stenting, and dural arteriovenous fistula coil embolization. A total of eight (9.3%) hemorrhagic complications were observed, two (3.6%) in the aspirin/clopidogrel group and six (19.4%) in the aspirin/prasugrel group (p=0.02). No differences were noted in hemorrhage rates for each procedure between treatment groups, nor were there any differences in thrombotic complications between groups. Conclusion Our results suggest that DAPT with aspirin/prasugrel may predispose to a higher risk of hemorrhage during neurointerventional surgery compared with DAPT with aspirin/clopidogrel.