Rationale Transcranial Doppler (TCD) monitoring during intravenous tissue plasminogen activator (i.v.-tPA) infusion increases recanalization rates in acute ischemic stroke. Addition of perflutren-lipid microspheres MRX-801 (microS) may further enhance the process of recanalization. This article describes the design of the Transcranial Ultrasound in Clinical SONolysis (TUCSON) trial. Aims and Design TUCSON is a phase I-II, randomized, placebo-controlled, open-label, safety, dose-escalation clinical trial of microS+TCD ultrasound (sonolysis). Patients with acute ischemic stroke and arterial intracranial occlusions are enrolled within 3 h of symptom onset. All patients receive standard i.v.-tPA and will be randomized to 90 min of continuous 2-MHz TCD+microS or 90 min of saline+brief TCD vessel assessments. The safety profile of four escalating dose tiers will be assessed. Arterial occlusions and recanalization are defined with the Thrombolysis in Brain Ischemia flow grades. Study Outcomes Safety is determined by the rates of symptomatic intracerebral hemorrhage within 36 h. Neurological deficits and outcomes are measured with the National Institute of Health Stroke Scale and modified Rankin Scale (mRS). The signal-of-efficacy is determined by rates of recanalization, dramatic or early clinical recovery within 2 h, clinical recovery at 24-36 h and independent outcome (mRS 0-2) at 90 days.