Administration of microbubbles (MB) may augment the effect of ultrasound-enhanced systemic thrombolysis in acute stroke. Bubble structural characteristics may influence the effect of MB on sonothrombolysis. We aimed to compare the effects of galactose-based air-filled MB (Levovist) and sulphur hexafluoride-filled MB (Sonovue) on recanalization and clinical outcome. One hundred thirty-eight i.v. recombinant tissue plasminogen activator-(tPA-) treated patients with middle cerebral artery (MCA) occlusion were studied. Presence and location of arterial occlusion and recanalization (RE) were assessed using the thrombolysis in brain ischemia (TIBI) flow grading system. Patients underwent 2 h of continuous transcranial Doppler (TCD) monitoring and received three bolus of MB after 2, 20 and 40 min of tPA bolus. Ninety-one patients received Levovist (LV) and 47 received Sonovue (SV). NIHSS scores were obtained at baseline and after 24 h. Modified Rankin Scale (mRS) score was used to assess outcome at 3 mo. Median admission NIHSS was 17. On TCD, 96 (69.6%) patients had a proximal and 42 (30.4%) a distal MCA occlusion. Age, baseline NIHSS, clot location, stroke subtypes and time to treatment were similar between LV and SV groups. Recanalization rates after 1 h (32.2%/35.6%), 2 h (50.0%/46.7%) and 6 h (63.8%/54.5%) were similar in LV/SV groups (p > 0.3). Clinical improvement (NIHSS decrease >or= 4 points) at 24 h was similar in both groups (54.9%/51.1%, p = 0.400), as well as symptomatic intracranial haemorrhage rate (3.3%/2.1%, p = 0.580) and in-hospital mortality (8.1%/9.3%, p = 0.531). Similarly, the type of MB administered did not affect long-term outcome after sonothrombolysis. Forty-four percent of patients in the LV group and 48.5% in the SV group achieved functional independence (mRS <or= 2) at 3 mo (p = 0.440). MB administration during sonothrombolysis is associated with a high RE rate. However, RE rates, clinical course and long-term outcome are comparable when administering galactose-based air-filled MB (Levovist) or sulphur hexafluoride-filled MB (Sonovue).