Background and Purpose: We prospectively evaluated the safety of aggressive mechanical disruption of thrombus following full-dose intravenous (IV) recombinant tissue plasminogen activator (rt-PA) to treat ischemic stroke in 24 patients with an initial National Institutes of Health stroke scale (NIHSS) score of ≥10. Methods: Clinical evaluations were performed at presentation and 24 hours, 7 to 10 days, and 1 to 3 months (using modified Rankin scale) after treatment. These end points were compared to matched historical controls treated with IV rt-PA alone. Results: Of the 24 patients, mechanical disruption was undertaken in 17 patients with persistent angiographic occlusion using microcatheter exploration (n = 3), angioplasty (n = 5), snare maneuvers (n = 7), and combination of both (n = 2). Partial or complete recanalization was observed in 10 of the 17 patients. Neurological improvement at 24 hours (≥4 point reduction in NIHSS score) was observed in 11 of 17 patients. Comparisons with matched controls suggest potential equivalence for symptomatic ICH (0% vs 12%), asymptomatic ICH (18% vs 15%), and early neurological improvement (65% vs 53%). Conclusion: The study shows that aggressive mechanical thrombus disruption in large artery occlusion in the setting of acute ischemic stroke is safe with acceptable rates of ICH and promotes angiographic recanalization.