Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis minimizes the risk of intracranial bleeding compared with systemic full-dose fibrinolytic therapy for pulmonary embolism (PE). However, major bleeding is nevertheless a potential complication. We analyzed the 150-patient SEATTLE II trial of submassive and massive PE patients to describe those who suffered major bleeding events following ultrasound-facilitated, catheter-directed, low-dose fibrinolysis and to identify risk factors for bleeding. Major bleeding was defined as GUSTO severe/life-threatening or moderate bleeds within 72 hours of initiation of the procedure. Of the 15 patients with major bleeding, four (26.6%) developed access site-related bleeding. Multiple venous access attempts were more frequent in the major bleeding group (27.6% vs 3.6%; p<0.001). All patients with major bleeding had femoral vein access for device delivery. Patients who developed major bleeding had a longer intensive care stay (6.8 days vs 4.7 days; p=0.004) and longer hospital stay (12.9 days vs 8.4 days; p=0.004). The frequency of inferior vena cava filter placement was 40% in patients with major bleeding compared with 13% in those without major bleeding (p=0.02). Massive PE (adjusted odds ratio 3.6; 95% confidence interval 1.01–12.9; p=0.049) and multiple venous access attempts (adjusted odds ratio 10.09; 95% confidence interval 1.98–51.46; p=0.005) were independently associated with an increased risk of major bleeding. In conclusion, strategies for improving venous access should be implemented to reduce the risk of major bleeding associated with ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. ClinicalTrials.gov Identifier: NCT01513759; EKOS Corporation 10.13039/100006522