The treatment options for high risk acute pulmonary embolism (PE) patients with failed systemic thrombolytic treatment (STT) is limited. The clinical use of catheter directed thrombolysis with the EkoSonic Endovascular System (EKOS) in this population has not been evaluated before. Catheter directed thrombolysis is an effective treatment modality for high risk PE patients with failed STT. Thirteen consecutive patients with failed STT were included in the study. EKOS catheters were placed and tissue plasminogen activator (t-PA) in combination with unfractionated heparin were given. Clinical and echocardiographic properties of the patients were collected before EKOS, at the end of EKOS and during the follow-up visit 6 months after discharge. The duration of EKOS treatment was 21.8 +/- 3.8 h and the total dose of tPA was 31.2 +/- 15.3 mg. One patient who presented with cardiac arrest died and the clinical status of the remaining subjects improved significantly. Any hemorrhagic complication was not observed. EKOS resulted in significant improvement of right ventricular functions and decrease of systolic pulmonary artery pressure. During a follow-up period of 6 months none of the patients died or suffered recurrent PE. In addition, echocardiographic parameters or right ventricular function significantly got better compared to in-hospital measurements. EKOS is an effective treatment modality for high risk PE patients with failed STT and can be applied with very low hemorrhagic complications.