Abstract Purpose To assess the safety of low-dose intra-arterial (IA) tirofiban bolus after unsuccessful mechanical thrombectomy in patients with ischemic stroke due to large artery occlusion in anterior cerebral circulation. Materials and Methods Patients with ischemic stroke who were treated with mechanical thrombectomy were enrolled in a multicenter registry. Low-dose tirofiban was injected into the residual arterial thrombus in patients after unsuccessful mechanical thrombectomy. The major safety measurement was defined as symptomatic intracranial hemorrhage (SICH). The functional outcome at 90 days was assessed with the modified Rankin Scale, and a score of 0–2 was defined as favorable. Results Of the 632 enrolled patients, 154 (24.4%) received IA tirofiban treatment. The SICH rate was 13.6% (21/154) in patients with tirofiban and 16.7% (80/478) in patients without tirofiban (P = .361). IA tirofiban was not associated with increased risk of SICH (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.36–1.31; P = .26). IA tirofiban treatment did not increase the risk of mortality at 90 days of the index stroke (OR, 0.66; 95% CI, 0.36–1.31; P = .15). Patients with large artery atherosclerosis stroke who were treated with tirofiban were associated with decreased risk of death (OR, 11.3% vs 23.4%; P = .042) compared to patients who were not treated with tirofiban. Conclusions Low-dose IA tirofiban administration may be relatively safe in patients with ischemic stroke after unsuccessful recanalization.