BACKGROUND: Neurocognitive late effects after childhood acute lymphoblastic leukemia (ALL) are well-documented, but their impact on quality of life (QOL) is not well understood. In this multi-site study, we examined the relative influence of neurocognitive functioning, steroid randomization (prednisone vs. dexamethasone), and demographic characteristics on QOL in first-remission survivors of childhood ALL. METHODS: Participants included 263 ALL survivors (ages 7-17 years at the time of evaluation; mean age at diagnosis 3.9 years) who were treated on similar legacy Children's Cancer Group chemotherapy protocols and did not receive cranial radiation. Children completed detailed neuropsychological performance tests. The Pediatric QOL Inventory was completed by children and their parents. Participants were a mean of 9 years from diagnosis at the time of assessment (with a range of 4 to 13 years). RESULTS: Children and their parents reported lower mean child psychosocial QOL than healthy population norms (p < 0.05), but were not in the impaired range. Physical QOL was similar to population norms. Though neurocognitive difficulties were predominantly mild for the sample as a whole, neurocognitive deficits, specifically problems in verbal cognitive abilities and visual-motor integration skills, were significantly associated with poor physical (p < 0.01) and Psychosocial QOL (p < 0.01). QOL was not associated with previous steroid randomization. CONCLUSIONS: ALL survivors with neurocognitive deficits are at risk for poor QOL, with broad implications for their physical, social, and school functioning. Copyright (c) 2014 John Wiley & Sons, Ltd.