Venocclusive disease (VOD) of the liver is the major dose-limiting complication of pretransplant regimens for bone marrow transplantation. Recent reports from different groups point to the involvement of the hemostatic mechanism in the development of VOD. We measured the naturally occurring anticoagulants protein C, antithrombin III, and protein S in 45 patients undergoing bone marrow transplantation for hematologic malignancies before cytoreductive therapy and after transplant. The aim of this prospective study was both to evaluate the status of the naturally occurring anticoagulant pathway in patients who develop VOD compared with patients who do not, and to find a predictive marker of VOD. In transplant patients, protein C decreased from before cytoreductive therapy to posttransplant, whereas protein S and antithrombin III did not. In a multivariate analysis, protein C was the only variable that could independently discriminate between VOD and non-VOD patients at all times. Discriminant function analysis established that low protein C levels before cytoreductive therapy predicted the occurrence of VOD with good sensitivity and specificity.