Changes in intellectual function during the course of treatment for acute lymphocytic leukemia were studied. Twenty-four children had baseline psychological evaluations and annual reevaluations for 3–6 years postdiagnosis. Treatment in all patients included combination chemotherapy, 2.400 cGy prophylactic cranial irradiation, and intrathecal methotrexate. Central Nervous System (CNS) relapse occurred in eight of these children. It was then treated with 3,000 cGy cranial plus 1,800 cGy spinal irradiation. Patients who remained in continuous complete remission showed no decline in global intelligence quotient (IQ). Patients who experienced CNS relapse had a mean decline of 16 IQ points by 3 years postdiagnosis and the long-term survivors displayed a mean loss of 25 IQ points 5–6 years postdiagnosis. Three of the five long-term survivors of CNS relapse function within the retarded range of mental ability and require special education. The other two have learning problems and display poor academic performance relative to same-age peers. There was no association noted between age at diagnosis and ultimate loss of IQ points. This prospective study suggests that children who receive a second course of cranial irradiation for treatment of CNS relapse are at high risk for significant and progressive intellectual loss.