A 7-month-old baby girl with acute lymphoblastic leukemia (ALL) presented with bulging anterior fontanelle after completing the first and second courses of high-dose methotrexate (HD-MTX) chemotherapy. Between courses, the infant recovered and was discharged. Prior to the third and fourth HD-MTX courses, the baby girl was administered infusions of dexamethasone, which prevented recurrence of neurological side effects observed after the first and second courses of HD-MTX. To our knowledge, this is the first reported case of HD-MTX-induced idiopathic intracranial hypertension in infants, and that prophylactic use of dexamethasone can be applied to prevent acute intracranial hypertension following HD-MTX infusion.