Veno-occlusive disease (VOD) is a serious complication of intensive chemotherapy regimens used in hematopoietic stem cell transplantation (HSCT). Incidence ranges from 10–60% (Chopra et al., 2000). Despite numerous therapeutic attempts described such as rtPA, TIPS and defibrotide mortality remains 80% (Fried et al., 1996). Risk factors for developing VOD are previous high-dose chemotherapy, unrelated donor transplants and busulfan-based conditioning regimens. In face of the frequency and high mortality due to absence of effective therapeutic options there is need for prophylaxis. We incorporated defibrotide into the supportive regimen for high risk patients undergoing a HSCT with busulfan containing conditioning regimens. From 01/2003 to 08/2004 44 patients (median age 52y, 24 male) receiving a busulfan containing regimen for HSCT (2 autologous, 42 allogeneic, 23 unrelated donors) were treated prophylactically with defibrotide as 800mg/24h continuous infusion from start of conditioning chemotherapy up to day +21 (group 1). Underlying diseases were: 10 AML, 24 NHL, 3 HD, 6 MM, 1 CML. Median number of previous regimens were 3. 27 patients had high-dose chemotherapies followed by autologous HSCT as prior therapy. From 07/2001 to 12/2002 16 patients (median age 45y, 11 male) receiving busulfan-based conditioning for allogeneic HSCT (7 unrelated donors) received heparin (300IE/h) for prophylaxis of VOD and catheter related thrombosis (group 2). Disease entities were 7 AML, 7 NHL, 1 HD, 1 ALL. Median number of previous regimen was 3. 11 patients had high-dose therapies followed by autologous HSCT as prior therapy. While in the latter group 1/16 patients developed and finally died of VOD, 3/44 in the defibrotide group did so. Date of VOD diagnosis in the patient not prophylatically treated with defibrotide was day +13 after HSCT compared to day +21, +25 and +27 in patients who received defibrotide prophylaxis. There were no serious adverse events (e.g. bleeding) attributable to defibrotide. Overall incidence of VOD in both groups is low (6,8% group 1; 6,3% group 2). Although patients in group 1 were at high risk of VOD, no VOD occurred during the period of defibrotide prophylaxis. We conclude that defibrotide is save and efficient in prevention of VOD. Defibrotide delayed the onset of VOD beyond its application. However, with defibrotide prophylaxis late onset of VOD has to be encountered. The optimal application period has to be determined.