The objective was to analyze risk factors for veno-occlusive disease of the liver (VOD) after allogeneic bone marrow transplantation. A cohort of 1717 recipients of HLA-identical sibling transplants for leukemia between 1988 and 1990, in 200 transplant teams worldwide, was studied. Patients were scored as having VOD if liver tissue showed typical histologic features or if they had all three of the following: (1) jaundice; (2) hepatomegaly and right upper quadrant abdominal pain; and (3) ascites and/or unexplained weight gain. Patients surviving more than 7 days post-transplant without histologic or any of these clinical features of VOD were classified as not having VOD. Patient-, disease- and transplant-related characteristics of 95 patients with VOD were compared to those of 1514 without VOD. Variables correlated with an increased risk of VOD were: pretransplant conditioning with busulfan and cyclophosphamide compared to total body radiation (relative risk (RR) 2.8; P < 0.0001), pretransplant fungal infection (RR 4.1; P = 0.011), pretransplant Karnofsky performance score < 90% (RR 1.9; P = 0.012), prior liver disease (RR 1.9; P = 0.05) and age > 20 years (RR 1.8; P = 0.05). In patients receiving radiation for conditioning, intravenous immune globulin decreased VOD risk (RR 0.26; P = 0.003). This analysis identifies risk factors for VOD. The data suggest several strategies for modifying transplant regimens to reduce VOD risk and which patients might be suitable subjects for trials of strategies of VOD prevention.