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Health-related quality of life (HRQL) improved progressively during therapy and beyond in children treated for acute lymphoblastic leukemia on the Dana-Farber Cancer Institute (DFCI) 95-01 protocol. This study aimed to validate that trajectory in a successor study (DFCI 00-01) and to compare the HRQL of patients in the 2 studies. Children aged above 5 years were assessed during each phase of treatment (N=4) and 2 years after completion of therapy. Health status and HRQL were measured using Health Utilities Index (HUI) instruments, HUI2 and HUI3. Quality-adjusted life years (QALYs) were calculated and compared with the general population, and patients treated on DFCI 95-01. Over 5 intervals and 758 HUI assessments, mean HRQL increased progressively from remission induction to the time after treatment (P<0.001). During intensification, high-risk patients had lower HRQL than standard-risk patients (P<0.001). During remission induction, patients on DFCI 95-01 had lower HRQL than patients on DFCI 00-01. Patients on DFCI 00-01 had ~0.2 and 0.3 fewer QALYs than controls, measured by HUI2 and HUI3, respectively. QALYs for DFCI 00-01 patients during treatment were similar to those for DFCI 95-01 patients. The trajectory of improvement in HRQL during the treatment of acute lymphoblastic leukemia in children was confirmed.