About 20% of patients with transient leukemia (TL), which is a disease noted in Down syndrome, are reported to develop hepatic fibrosis, which has a poor prognosis. The clinical factors related to the poor prognosis of TL were retrospectively analyzed in 25 patients, and criteria for starting chemotherapy were established. The initiation of chemotherapy was recommended when two or more of the following categories were fulfilled in the process of the disease: (1) a reduced hepatic functional reserve estimated by direct bilirubin, prothrombin time, and the presence of ascites, (2) an elevated level of hyaluronic acid (>500 U/mL), (3) respiratory failure or poor sucking associated with hepatosplenomegaly, and (4) demonstration of fibrosis by liver biopsy. When these criteria were applied to our cases, all patients who received chemotherapy remained alive. Our criteria are useful for selecting patients with TL at high risk of developing hepatic fibrosis and for starting chemotherapy.