Introduction: Prompt and effective treatment of pulmonary embolism (PE) is essential to prevent morbidity and mortality. We aim to evaluate and compare the effectiveness of two FDA-approved catheter-based therapies (CBT) for acute high-risk PE: ultrasound-assisted catheter-directed thrombolysis EKOS (EKOS Corporation, Bothell, WA) and Penumbra Indigo aspiration thrombectomy (Penumbra Inc., Alameda, CA, USA). Methods: Patients with acute high-risk submassive or massive PE who underwent CBTs between 09/2014 and 08/2022 at our institution were identified. The primary efficacy outcome was the change in the echocardiographic RV/LV diameter ratio within 48 to 72h of procedure. Results: A total of 189 patients underwent EKOS (n=119) or Penumbra (n=70) for submassive (n=175) and massive (n=14) PE (Table). Both groups had similar demographics and clinical characteristics except for prior DVT. Mean age was 60.6±14.3 years old and 55.6% were male. The RV/LV ratio showed significant improvement post intervention, with 21.2% decrease in the EKOS group (EG) and 35.6% in the Penumbra group (PG). The PG had a greater decrease in RV/LV (median change 0.396 (IQR, 0.347) vs. 0.207 (IQR, 0.306), p<0.001). In the cohort, 25 adverse events were reported (13.2%). The rate of complications did not differ between the 2 groups, with 15.1% in EG and 10% in PG. In terms of bleeding complications, GUSTO moderate bleeding was observed in 8 cases (5 in EG and 3 in PG), while severe bleeding was observed in 3 (2 in EG and 1 in PG), including 1 intracranial hemorrhage in the PG. ICU admissions were higher in the PG (p<0.001), but median hospital and ICU stays were comparable. No significant difference was found in the rate of in-hospital mortality (2.5% in EG, 4.3% in PG, p=0.672). Conclusion: Both CBT options are promising for treating submassive PE, with efficacy outcomes favoring Penumbra thrombectomy. Longer follow-up and randomized controlled trials are needed for definitive conclusions.