The aim was to demonstrate the safety and efficacy of continuous ultrasound monitoring of the artery occlusion area (sonothrombotripsy) in patients with acute middle cerebral artery (MCA) occlusion. A total of 52 consecutive patients with acute MCA occlusion were included in the thrombotripsy group. Doppler monitoring of the region of occlusion was performed for up to 45 min. The control group was created from the NAIS study database. Patients were matched for their vascular status, age, sex, artery occlusion, NIHSS at admission, rt-PA treatment and time to the first ultrasound examination. The number of recanalized arteries at 6 and 24 h after the onset of symptoms, the number of independent patients (mRS 0-2 versus 3-6) after 90 d, and the number of serious adverse events were statistically evaluated. In the thrombotripsy group, 19 patients (36.5%) had complete recanalization and 27 (51.9%) patients had partial recanalization at 1 h after the start of the TCCS monitoring. Higher recanalization rates at 6 and 24 h after stoke onset were also seen compared with controls (69.2% versus 7.7% and 92.3% versus 61.5% complete recanalizations, respectively, p < 0.05). Independence (mRS 0-2) at day 90 was achieved by 61.5% of the thrombotripsy patients and 32.7% controls, p < 0.05, odds ratio 1.88 (95% confidence interval = 1.23 - 2.90). In both groups, two symptomatic intracerebral hemorrhages and one symptomatic brain edema occurred. Sonothrombotripsy with diagnostic transcranial duplex technology is safe and may offer benefit in addition to standard of care stroke treatment.