Background First-pass successful reperfusion (FPSR), defined as a successful/complete reperfusion achieved after a single thrombectomy pass, is predictive of favorable outcome in patients with acute ischemic stroke with large-vessel occlusion. It is unknown whether intravenous tirofiban is effective in increasing the rate of FPSR in acute anterior large-vessel occlusion stroke. Methods and Results Patients who had acute large-vessel occlusion stroke presenting within 24 hours and underwent endovascular thrombectomy were analyzed from the RESCUE BT (Intravenous Tirofiban for Patients With Large Vessel Occlusion Stroke) clinical trial, of which the main analysis was neutral. The RESCUE BT trial randomized patients to receive either intravenous tirofiban or placebo before endovascular thrombectomy. The primary end point was FPSR, defined as successful reperfusion (extended thrombolysis in cerebral infarction scale 2b50, 2c, or 3) at first thrombectomy attempt. A modified Poisson regression analysis assessed the association between intravenous tirofiban treatment and FPSR. Of 948 enrolled patients, 463 patients were randomized to the tirofiban group and 485 to the placebo group. The mean age was 67 years, and 41.0% of the patients were women. FPSR was achieved more often in the tirofiban group (30.5% versus 23.5%; adjusted risk ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04). FPSR was associated with a favorable shift to lower modified Rankin Scale disability levels at 90 days (common odds ratio, 1.42 [95% CI, 1.08-1.86]; P=0.01). Conclusions In this post hoc analysis of the RESCUE BT trial, treatment with intravenous tirofiban before endovascular thrombectomy was associated with increased FPSR in patients with acute ischemic stroke due to large-vessel occlusion in the anterior circulation. FPSR was associated with reduced 90-day levels of disability. Registration URL: http://chictr.org; Unique Identifier: ChiCTR-INR-17014167.