Introduction: The degree of culprit artery stenosis affects the risk of early neurological deterioration (END) after acute ischemic stroke (AIS). The TREND trial demonstrated the efficacy of tirofiban in preventing END in patients with AIS. We aimed to investigate whether the degree of intracranial artery stenosis affects the efficacy of tirofiban in preventing END in patients with AIS. Patients and Methods: We conducted a post hoc analysis of the TREND trial, which enrolled patients within 24 h of onset and randomly allocated to receive intravenous tirofiban or oral aspirin. We stratified the stenosis degrees into three subgroups: no stenosis, mild-to-moderate stenosis (stenosis <70%), and severe stenosis or occlusion (stenosis >= 70%). The primary endpoint is END4 defined as an increase of the NIHSS >= 4 within 72 h after randomization. Secondary outcomes include END2 (defined as an increase of NIHSS >= 2) within 72 h after randomization, the proportion of mRS 0-1 and 0-2 at 90 days. Results: A total of 296 patients were analyzed. In patients with severe stenosis or occlusion, tirofiban significantly reduced the incidence of END4 (5.7% vs 30.8%, adjusted OR 0.156, 95% CI 0.028-0.873, adjusted p = 0.034), whereas its effects in preventing END4 were similar to those of aspirin in patients with no stenosis (2.4% vs 4.6%, adjusted OR 0.193, 95% CI 0.018-2.083, adjusted p = 0.175) or mild-to-moderate stenosis (2.9% vs 10.0%, adjusted OR 0.171, 95% CI 0.015-1.943, adjusted p = 0.155). The p value for interaction between stenosis subgroups and treatment was 0.513. Furthermore, tirofiban significantly reduced the incidence of END2 in patients with mild-to-moderate stenosis (5.9% vs 22.5%, OR 0.146, 95% CI 0.022-0.951, adjusted p = 0.044) and severe stenosis or occlusion (11.4% vs 43.6%, adjusted OR 0.140, 95% CI 0.036-0.540, adjusted p = 0.004). A significant improvement in favorable outcomes with a 90-day mRS of 0-1 was observed only in patients with mild-to-moderate stenosis (85.3% vs 70.0%, adjusted OR 4.617, 95% CI 1.077-19.798, adjusted p = 0.039). Discussion and conclusion: Tirofiban may significantly reduce the incidence of END in patients with severe arterial stenosis or occlusion. Further studies are required to confirm the effects of intracranial artery stenosis on the benefits of intravenous tirofiban. Trial registration: ClinicalTrials.gov; identifier: NCT04491695.