Recent findings presented at the 2012 International Stroke Conference suggest that the application of a new hands-free ultrasound thrombolytic device in combination with tissue-type fibrinogen activator (tPA) has a good safety profile and a high rate of revascularization. This combination therapy warrants further evaluation in a phase III effectiveness trial. When used in combination with intravenous (IV)-tPA, an FDA-approved handheld transcranial Doppler (TCD) ultrasound device improves recanalization. The Combined Hands-Free Transcranial Ultrasound and Systemic t-PA Cerebral Hemorrhage Thrombolysis (CLOTBUST-HF) study is the first multicenter, open-label, antegrade safety study performed in humans; the tPA combined with a hands-free ultrasound device was evaluated in patients with ischemic stroke caused by proximal intracranial vascular obstruction. This hands-free device consists of 18 ultrasound probes; it can be activated continuously to provide therapeutic ultrasound to the overall intracranial circulation. All subjects were treated with standard dose IV tPA followed immediately by 2 hours of 2-MHz ultrasound. The primary referral was symptomatic intracranial hemorrhage (sICH). All subjects were evaluated for vascular opening and recanalization before and after treatment by standardized TCD or CT angiography. National Institutes of Health Stroke Scale (NIHSS) scores were collected at 2 hours, and modified Rankin score (mRS) was tallied at 90 days. Results A total of 20 patients were included in the study (60% male, mean age 63±14 years, median NIHSS=15). Pre-treatment arterial obstruction sites: 70% were middle cerebral artery (MCA), 15% were end of internal carotid artery (ICA), and 15% were vertebral artery. tPA to median time to initiation of ultrasonic thrombolysis (IQR) was 22 minutes. All patients tolerated the 2-hour ultrasound treatment and no patient experienced sICH. there were no serious adverse events associated with the device under investigation.