Objective: To evaluate the efficacy of ultrasound-accelerated catheter-directed thrombolysis (UACDT) in the treatment of patients with massive and submassive pulmonary embolism (PE). Method: Twenty-two patients (13 males and nine females; age range, 38 to 71 years; mean age, 53.7 years) with massive or submassive PE were treated with UACDT with the EKOS EkoSonic (R) system. All patients exhibited acute symptoms, computed tomography (CT) evidence of large thrombus burden, and evidence of right ventricular (RV) dysfunction and/or failure. Clinical outcomes and complications, RV pressures, and thrombus clearance were evaluated. Results: Treatment of 22 patients resulted in complete thrombus clearance (>= 90%) in 77.2% of the patients, and near-complete (50% to 90%) clearance in 22.8%. The median tissue plasminogen activator (tPA) dose for all patients in our study was 21.0mg (range 16 to 35 mg) and the median infusion time was 20.5 hours (range 12 to 28 hours). Measurements before and after treatment showed a decrease in pulmonary artery pressure (67 +/- 14 to 34 +/- 11 mmHg [systolic], p<0.001). The RV/LV ratio decreased from 1.29 +/- 0.17 to 0.92 +/- 0.11 at follow-up (p<0.001). Modified Miller score was significantly reduced (from 28 +/- 4 to 13 +/- 5, p<0.001) in 21 of 22 (95%) patients who survived to discharge. There were only two minor access site bleeding complications, neither requiring transfusion. Conclusion: This study demonstrates safety and effectiveness of UACDT in patients with acute PE with a large thrombus burden.