In SEATTLE II, major bleeding occurred in 10% of patients undergoing ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. Nearly a quarter of these major bleeds were associated with vascular access, including one GUSTO severe/life-threatening bleed. No patient suffered ICH, and there were no fatal bleeds. Factors most strongly associated with an increased risk of bleeding were the presence of massive PE and multiple attempts at obtaining venous access. All patients with major bleeding had femoral access for placement of the ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. Major bleeding was associated with a longer length of hospital stay and more frequent insertion of IVC filters.