Introduction: The standard management of childhood acute lymphoblastic leukemia with hyperleukocytosis is unclear and its treatment has focused on prompt leukocytoreduction. Cytoreductive therapies have been used for the prevention of tumor lysis syndrome, but the outcomes have been variable and their benefits have not been proven in controlled clinical trials. This condition needs further investigation to develop effective therapeutic strategies. Methods: In the present prospective trial, 15 children with acute lymphoblastic leukemia and hyperleukocytosis (range 101–838 × 109/l) were treated with intravenous low-dose prednisone continuous infusion (6 mg/m2/24 h). Doses were increased daily and on approximately the fifth day, the full dose of prednisone (60 mg/m2/day) was applied. Results: The mean reduction in white blood cell count achieved by this treatment was 34.4% on first day, 56.9% on second day and 76.6% on third day. The treatment was well tolerated. None of the 15 patients developed life-threatening metabolic disorders or required dialysis. Conclusions: Intravenous low-dose prednisone continuous infusion treatment can prevent the progression to tumor lysis syndrome and it may be used for the patients presenting with white blood cell counts between 100 and 400 × 109/l in centers where leukoapheresis is not readily available.