We present two children with acute lymphocytic leukemia who developed leukoencephalopathy following administration of a combination of intravenous ara = C and methotrexate during the consolidation phase of chemotherapy. Cranial magnetic resonance imaging showed widespread, abnormally high signal intensity in the deep white matter in both patients, though one patient had normal cranial computed tomographic scan. Treatment was modified, symptoms resolved in 1 to 2 weeks, and the white-matter changes resolved over 6 to 12 months. Intravenous cytarabine and methotrexate appear to act synergistically to enhance the potential for central nervous system toxicity. Awareness of this potentially serious complication of chemotherapy can facilitate timely recognition of leukoencephalopathy with the use of magnetic resonance imaging.