We observed that all patients with major bleeding had femoral access for placement of the ultrasound-facilitated, catheter-directed, low-dose fibrinolysis compared with 84% of those without major bleeding. Femoral access attempts are associated with an increased risk of unintended femoral artery or side branch puncture. Alternative access sites, such as the internal jugular vein, may reduce the risk of major bleeding in patients undergoing ultrasound-facilitated, catheter-directed, low-dose fibrinolysis.