Background: Stroke is considered the second most common cause of death and the major cause of disability worldwide. Sonothrombolysis via improving the effectiveness of intravenous thrombolysis may be an effective treatment through enhancing early arterial recanalization. Objectives: To evaluate the efficacy and safety of sonothrombolysis in treatment of acute ischemic stroke. Patients and Methods: Patients with acute first ever ischemic stroke affecting the main stem of middle cerebral artery (MCA), within 4.5 hours following stroke onset were classified into 3 groups: 20 patients treated with both sonothrombolysis and tPA, 20 patients with tPA alone and 20 patients with sonolysis alone when tPA is contra-indicated or can?t be achieved. Patients with indefinite time of onset of stroke, Poor temporal window, or stroke due to occlusion of intracerebral arteries rather than MCA were excluded. Results: A considerable improvement of the degree of recanalization of MCA is observed for group (I), with (55 %) of patients had a complete recanalization after 1 hour compared to (35 %) for group II and (15 %) for group III. After 24 hours, full recanalization had been increased to involve (75%)of patients in group I. There was also a considerable clinical improvement as compared to the baseline evaluation scores with significant statistical difference after one hour for sonothrombolysis group and this improvement was maintained after 24 hours with statistically significant difference. After 1 hour, (25%) of patients in group I had a full clinical recovery compared to (10%) in group II and no patients in group III with a statistically significant difference for group I. After 24 hours, more patients had a full clinical recovery in group I (45%). Hemorrhagic transformation occurred in (10%) ofpatients in group I versus (5%) in group II without statistically significant difference. Conclusion: Sonothrombolysis can be used for patients with acute ischemic stroke safely without any further delay with a substantial improvement of the degree of recanalization of MCA and considerable clinical improvement.