The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continuous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCI scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the posttherapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients as an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer posttherapeutic interval.