Transcranial color-coded real-time sonography (TCCS) is an emerging diagnostic technique that allows noninvasive imaging of intracranial vessels within parenchymal structures. However, in some patients, transcranial ultrasound is particularly hindered by insufficient ultrasound penetration through the temporal bone. The present study evaluates whether or not application of an echo-contrast agent in ultrasound-refractory patients with middle cerebral artery (MCA) trunk occlusion enhances image acquisition enough to yield accurate diagnoses. Contrast-enhanced (CE) TCCS examinations, computed tomography scans and angiographic studies were performed in 20 patients with clinical symptoms suggestive of MCA occlusion within 12 h of the onset of symptoms. For comparison, 20 control persons without history or clinical signs for cerebrovascular diseases were examined using CE-TCCS. In none of the patients or control subjects did unenhanced TCCS investigations depict any color-coded vascular signal of an intracranial vessel. After application of 9 mL of 400 mg/mL galactose-based microbubbles, CE-TCCS was performed. In subjects with MCA occlusion, CE-TCCS examinations were repeated within 24 h, 48 h and 5 days after stroke. In stroke patients (n = 20), CE-TCCS showed an occluded MCA main stem in 11 patients, and this vessel was clearly demonstrable on the unaffected side. On the affected side, the posterior cerebral artery (PCA) and anterior cerebral artery (ACA) could be visualized in 8 of 11 subjects; in 3 patients, at least 1 of these vessels was detectable. Angiographic studies confirmed the diagnosis of MCA trunk occlusion in all 11 individuals. In follow-up investigations, 3 stroke patients had angiographic and CE-TCCS examinations consistent with vessel reperfusion. Nine stroke patients had a patent MCA shown in angiographic and CE-TCCS examinations. In the control group, the MCA trunk could be visualized in all subjects by CE-TCCS. CE-TCCS is a sensitive and specific ultrasound method for the diagnosis of MCA trunk occlusion that overcomes the anatomical hindrance of inadequate acoustic bone window. This technique may help to identify patients suitable for thrombolytic therapies and monitor their response.