Recombinant tissue plasminogen activator (rt-PA) is an effective treatment for veno-occlusive disease (VOD) after bone marrow transplantation (BMT). However rt-PA therapy is limited by the risk of hemorrhagic complications. There is little guidance about the use of rt-PA for patients with severe VOD and severe hemorrhage. We report the case of a 16-year-old woman who developed severe VOD associated with life-threatening hemorrhagic cystitis (HC). A dramatic improvement in VOD was obtained after administration of recombinant tissue plasminogen activator (rt-PA). HC was managed with continuous bladder irrigation and blood transfusions. Administration of rt-PA was followed by a moderate increase in blood transfusion requirement but rt-PA did not cause dramatic aggravation of the HC. We conclude that severe HC might not be a contraindication to rt-PA therapy and such patients can be included in randomized trials conducted to determine the efficacy and risk benefit of rt-PA therapy for VOD.