ObjectivesTo provide one of the first prospective reports examining neuropsychological outcomes for children treated with 1800 cGy whole brain radiotherapy (WBRT) and prophylactic chemotherapy versus prophylactic chemotherapy alone for acute lymphoblastic leukemia (ALL). Acute and long‐term neuropsychological toxicities associated with WBRT are compared. MethodsThis multisite study included 188 children, ages 4–21 years at enrollment, who were assessed with standardized neuropsychological tests at 9, 21, and 48 months after diagnosis with intermediate risk ALL. All participating children were receiving treatment on a parent study CCG105. ResultsVerbal intelligence (VIQ) scores for children receiving WBRT was significantly lower than VIQ for prophylactic chemotherapy at the 48‐month time point (p < 0.05). A significant cross‐level interaction between time since diagnosis and treatment condition was observed (p < 0.05). WBRT did not result in differences in PIQ; both groups of children demonstrated comparable increases in PIQ. Neuropsychological findings at 48 months after diagnosis indicated diminished performance in neuromotor, visual–motor coordination, and executive functioning for children receiving WBRT. Academic achievement was unaffected by WBRT at 4 years after diagnosis. ConclusionsThe measurement of verbal and performance IQ as a primary endpoint in ALL clinical trials is critical to characterizing neuropsychological late effects. A trajectory of decline in neuropsychological functioning, specifically verbal IQ, was observed. Missing data within the trial occurred at random and did not impact results observed. The impact of WBRT becomes evident at 48 months after diagnosis, suggesting the need for long‐term follow‐up beyond the time frame typically used in Phase III trials. Copyright © 2014 John Wiley & Sons, Ltd.