Background Sonothrombolysis is safe and may increase the likelihood of early recanalization in acute ischemic stroke patients. Aims In preparation of a phase III clinical trial, we contrast the likelihood of achieving a sustained recanalization and functional independence in a post hoc subgroup analysis of patients randomized to transcranial Doppler monitoring plus intravenous tissue plasminogen activator (sonothrombolysis) compared with intravenous tissue plasminogen activator alone in the CLOTBUST trial. Methods We analyzed the data from all randomized acute ischemic stroke patients with pretreatment National Institutes of Health Stroke Scale scores >= 10 points and proximal intracranial occlusions in the CLOTBUST trial. We compared sustained complete recanalization rate (Thrombolysis in Brain Ischemia flow grades 4-5) and functional independence (modified Rankin Scale 0-1) at 90 days. Safety was evaluated by the rate of symptomatic intracranial hemorrhage within 72 h of stroke onset. Results Of 126 patients, a total of 85 acute ischemic stroke patients met our inclusion criteria: mean age 71 +/- 11years, 56% men, median National Institutes of Health Stroke Scale 17 (interquartile range 14-20). Of these patients, 41 (48%) and 44 (52%) were randomized to intravenous tissue plasminogen activator alone and sonothrombolysis, respectively. More patients achieved sustained complete recanalization in the sonothrombolysis than in the intravenous tissue plasminogen activator alone group (38.6% vs. 17.1%; P = 0.032). Functional independence at 90 days was more frequently achieved in the sonothrombolysis than in the intravenous tissue plasminogen activator alone group (37.2% vs. 15.8%; P = 0.045). Symptomatic intracranial hemorrhage rate was similar in both groups (4.9% vs. 4.6%; P = 1.00). Conclusions Our results point to a signal of efficacy and provide information to guide the subsequent phase III randomized trial of sonothrombolysis in patients with severe ischemic strokes.