Prophylactic treatment of the central nervous system (CNS) in childhood leukemia and non-Hodgkin lymphoma (NHL) has negative effects on intelligence. We investigated the clinical significance of this finding by comparing the effect of different types of CNS prophylaxis on the survivor's learning capabilities. To isolate the effect of different types of CNS prophylaxis from other treatment and disease variables on learning problems, children treated for leukemia or NHL who received CNS prophylaxis with cranial irradiation (n = 30) or without cranial irradiation (n = 36) were compared with children treated for solid tumors who received systemic chemotherapy without any CNS treatment (n = 30) and with matched healthy controls (n = 265). The identification of learning problems was based on the school system's assessment. Parents and teachers reported on the child's educational status in a standardized way. Learning problems were found in 80% of children who received CNS prophylaxis with cranial irradiation. This was significantly higher than the 14% found in children treated with CNS prophylaxis without cranial irradiation (P < 0.000). The prevalence of learning problems in this latter group did not differ significantly from that in childhood cancer survivors without any form of CNS prophylaxis (20%) and in healthy matched controls (17%). We conclude that the high prevalence of learning problems in survivors of childhood leukemia and NHL is directly related to CNS prophylaxis with cranial irradiation and not to CNS prophylaxis per se or to other treatment and disease variables.