Acute massive pulmonary embolism (PE) is a life-threatening condition that requires prompt and aggressive interventions, including anticoagulation, catheter-directed thrombolysis (CDT), mechanical thrombectomy, or surgical thromboembolectomy. The aim of this study was to evaluate the treatment outcome in patients with massive PE who were treated with either ultrasound-accelerated thrombolysis using the EkoSonic Endovascular System (EKOS) or CDT intervention. During a recent 10-year period, the clinical records of all patients with massive PE undergoing catheter-directed interventions were evaluated. Patients were divided into two treatment groups: EKOS versus CDT interventions. Comparisons were made with regard to the treatment outcome between the two groups. Twenty-five patients underwent 33 catheter-directed interventions for massive PE during the study period. Among them, EKOS or CDT was performed in 15 (45%) and 18 (55%) procedures, respectively. In the EKOS group, complete thrombus removal was achieved in 100% cases. In the CDT cohort, complete or partial thrombus removal was accomplished in 7 (50%) and 2 (14%) cases, respectively. Comparing treatment success based on thrombus removal, EKOS treatment resulted in an improved treatment outcome compared with the CDT group ( p ≤ .02). The mean time of thrombolysis in EKOS and CDT group was 17.4 ± 5.23 and 25.3 ± 7.35 hours, respectively ( p = .03). The mortality rate in the EKOS and CDT group was 9.1% and 14.2%, respectively (not significant). Treatment-related hemorrhagic complication rates in the EKOS and CDT group were 0% and 21.4%, respectively ( p = .02). A significant reduction in Miller scores was noted in both groups following catheter-based interventions. No significant difference in relative Miller score improvement was observed between groups. Ultrasound-accelerated thrombolysis using the EkoSonic system is an effective treatment modality in patients with acute massive PE. When compared with CDT, this treatment modality provides similar treatment efficacy with reduced thrombolytic infusion time and treatment-related complications.