Seven patients (median NIHSS = 16) were randomized to IV (N = 4) or IA (N = 3) TPA. There were no significant differences in the presentation NIHSS, time to presentation, or time to treatment between the two groups. Hemorrhage was noted in one patient in the IA group (asymptomatic) and one patient in the IV group (symptomatic). Recanalization was seen in all patients treated with IA TPA and none treated with IV TPA (P = 0.03, Fisher's Exact test). In conclusion, we found that it is feasible to conduct a trial comparing IV vs. IA TPA in ischemic stroke patients with major vessel occlusion presenting <3 h from onset. Patients treated with IA TPA showed a trend toward higher rate of recanalization. A larger trial may be designed to test safety and effectiveness of IA TPA in this specific group of stroke patients.