: Guidelines-recommend thrombolytic therapy for pulmonary embolism in patients with severe hemodynamic compromise and low risk of bleeding. Thrombolytics in submassive pulmonary embolism have an unfavorable risk/benefit ratio and remain controversial. Based on our experience with extensive, lower extremity thrombi, nine patients with symptomatic, submassive pulmonary embolisms (five medical, four surgical) were treated with low-dose alteplase (<10 mg/day, infused over 6 h per treatment). Alteplase was delivered by pulse spray and/or directed or undirected central venous catheters depending on clot size and location. All patients improved symptomatically and as determined objectively by pulmonary artery pressures and/or imaging, though acute benefits ranged from substantial to modest. One surgical patient required re-exploration for bleeding at the site of a recent retroperitoneal lymph node dissection. This experience may help guide the design of a randomized controlled trial to determine the safety and efficacy of low-dose alteplase for submassive pulmonary embolism.