Reduction of thrombus size and recanalization of vessels after deep vein thrombosis (DVT) are important goals to prevent recurrent thrombosis and development of postthrombotic syndrome. Thrombolysis is effective but concern for bleeding complications has limited its use in children. We retrospectively analyzed data for children with DVT treated with a low-dose systemic tissue plasminogen activator (tPA) regimen. Twenty-three pediatric patients (12 males and 11 females, median age 12 y) received low-dose systemic tPA, initiated at 0.03 to 0.06 mg/kg/h for a median of 24 hours (range 12 to 48 h). Of the 20 patients imaged within 24 hours of therapy, 6 (30%) showed partial to complete thrombus resolution. Eight patients subsequently received increased tPA at 0.12 mg/kg/h for an additional 24 hours (range 12 to 36 h). Six of these 8 (75%) patients responded to the increased dose. The overall response at the end of thrombolytic therapy was 59% (13/22). Two bleeding complications occurred without serious sequelae. Low-dose tPA administration leads to a substantial response rate although the risk of bleeding remains unclear. A prospective multicenter trial of low-dose thrombolytic therapy in children with acute DVT is warranted.