Descending iliofemoral thrombosis in children is a rare event. Anticoagulation therapy with low-molecular-weight-heparin is standard of care. However, patency cannot be achieved in all cases, increasing the risk for rethrombosis and postthrombotic syndrome. To reduce the risk of venous valve failure in adults, local catheter-directed thrombolysis is used to reopen vessels. Two adolescent girls (17 and 15 years old) presented with acute descending iliofemoral thrombosis of the left common iliac, external, and common femoral veins. Anticoagulation with enoxaparin was started until insertion of an EkoSonic Mach 4e catheter for ultrasound-assisted local thrombolysis with recombinant tissue plasminogen activator and administration of unfractionated heparin. Success was monitored by increases in D-dimer levels and ultrasound findings. After 24 hours respectively 48 hours, complete recanalization was obtained. No complication occurred except minimal local bleeding. Screening for hereditary thrombophilia revealed a heterozygous antithrombin mutation in 1 girl (ie, the 15-year-old). May-Thurner syndrome was identified in both girls, necessitating stenting of the left common iliac veins and continuation of anticoagulation therapy with enoxaparin and acetylsalicylic acid. No rethrombosis or complications occurred during the follow-up period. Ultrasound-assisted catheter-directed local thrombolysis with the EkoSonic Mach 4e system was effective in achieving immediate recanalization of the occluded veins and should be considered in children experiencing descending iliofemoral thrombosis. The fast recanalization might reduce the incidence of postthrombotic syndrome. May-Thurner syndrome is regularly found in these patients, and if present, requires stenting of the common iliac vein to avoid early reocclusion. However, long-term patency of iliac vein stenting in children remains to be examined.