Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.