Methotrexate (MTX) is an effective antimetabolite treatment for various oncological disorders including the central nervous system involvement (CNS) in widespread leukemia and CNS lymphoma. This form of treatment has a notable toxic effect on the nervous system, and the pediatric population seems to be more vulnerable to the neurologic toxicity of this drug. Though chronic leukoencephalopathy from an MTX regimen, especially when administered in conjunction with whole brain radiation, is well described, the acute manifestations are rare and not well understood. The diagnosis of acute focal symptoms from MTX treatment is especially difficult in patients who receive chemotherapy for neoplastic disorders and who may have many reasons for CNS involvement in general and parenchymal involvement in particular. We report the unusual clinical and neuro-imaging findings in a teenager with acute focal symptoms after MTX treatment for acute lymphoblastic leukemia.