The optimal treatment for intermediate-risk pulmonary embolism (PE) remains unclear. Our goal was to describe the safety and efficacy of the EkoSonic ultrasound-assisted catheter-directed thrombolysis system (EKOS Corporation, Bothell, Washington) in a real-world registry of patients with intermediate-risk PE. Fifty-three consecutive patients with intermediate-risk PE treated with ultrasound-assisted catheter-directed thrombolysis at Brigham and Women's Hospital from 2010 to 2014 were analyzed. The primary outcome was a change in directly measured pulmonary artery pressures as assessed using logistic regression with generalized estimating equations to account for serial measurements. Patients received an average of 24.6 ± 9 mg of alteplase using the EKOS catheter with an average treatment time of 15.9 ± 3 hours. After treatment, there was a 7.2- and a 11.4-mm Hg reduction in mean and systolic pulmonary artery pressure (95% confidence interval 4.7 to 9.7 mm Hg, p <0.001, and 95% confidence interval 7.8 to 15.0 mm Hg, p <0.001), respectively. In this cohort, 9.4% had any bleeding complication noted during their hospital stay. One patient's alteplase was prematurely discontinued for access site bleeding although no other interventions were required related to bleeding complications.