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Background Tirofiban is widely used in ischemic stroke, but its safety and efficacy during stenting of perforator-rich intracranial arteries are unclear. We speculate that prophylactic use of an intra-arterial bolus of tirofiban followed by intravenous maintenance after stenting of perforator-rich intracranial arteries may be safe and effective.Methods We retrospectively analyzed patients with atherosclerotic stenosis treated with stenting for perforator-rich intracranial arteries between January 2021 and December 2024. The tirofiban group received tirofiban 10 µg/kg immediately after stenting via a microcatheter into the target artery, followed by intravenous infusion of 0.1 µg/kg/min for 24–72 hours, while controls received dual oral antiplatelet therapy. The primary efficacy endpoints were the incidence of acute in-stent thrombosis (AST) within 30 min after stent implantation and ischemic stroke in the target vascular territory within 7 days post-procedure. Secondary endpoints included modified Rankin Scale score at 6 months and the incidence of in-stent restenosis. The primary safety endpoint was the incidence of symptomatic intracranial hemorrhage within 7 days post-procedure.Results 150 patients were included: 72 received tirofiban and 78 received dual antiplatelets. AST occurred in 2.8% of the tirofiban group versus 12.8% of controls (RR 0.89; 95% CI 0.82 to 0.98; P=0.02). AST was associated with uncontrolled diabetes, aspirin or clopidogrel resistance, and final residual stenosis. Recurrent ischemic stroke rates at 7 days (2.8% vs 6.4%; P=0.45), symptomatic intracranial hemorrhage (1.4% vs 1.3%), 6 month in-stent restenosis (7.1% vs 9.0%; P=0.68), and modified Rankin Scale scores at 6 months showed no significant differences.Conclusions Periprocedural intra-arterial with intravenous tirofiban reduced early AST, without increasing the risk of hemorrhage, for stenting of perforator-rich intracranial arteries.