The original definition of hepatic veno-occlusive disease (VOD), which is still widely accepted, includes onset of the clinical syndrome before day +20 following high-dose chemotherapy (HDC) and stem cell transplantation (SCT). We retrospectively identified four patients following HDC and SCT presenting with late onset VOD occurring at day +24, day +27, day +34 and day +42 post SCT. All patients had moderate VOD, with successful resolution of the VOD before day +100 with optimal supportive therapy. Common risk factors for VOD shared by all four patients included an older age (median age: 60 years), and use of a busulphan-containing regimen. Mean and maximum bilirubin levels for all patients during the VOD syndrome were 2.02, 1.76, 5.09, 2.87 mg/dl and 2.5, 2.2, 8.9 and 4.1 mg/dl, respectively, which correlated well with duration of VOD. All patients encountered platelet transfusion-dependent thrombocytopenia during VOD. Ursodeoxycholic acid was used as VOD prophylaxis beginning at a mean of 33 days prior to onset of VOD. As the cellular target of hepatic VOD is as yet unidentified, it is uncertain whether ursodiol or other common characteristics of patients with late onset VOD influence the pathogenesis and natural history of this disease. We believe that the uncommon clinical entity of late onset VOD, a potentially fatal regimen-related toxicity, should not be ignored as a diagnosis of liver disease after 3 or more weeks following HDC and SCT.