OBJECTIVES: To identify differences in health-related quality of life (HRQL) between 2 consecutive Dana Farber Cancer Institute (DFCI) protocols to treat acute lymphoblastic leukemia (ALL) diagnosed during childhood. METHODS: Children diagnosed with standard and high risk ALL and treated according to DFCI protocol 95-001 or 00-001 at 5 and 9 Centres, respectively, in Canada and the USA were eligible for study. Parents of patients completed Health Utilities Index (HUI) questionnaire assessments during each of 4 major phases of therapy (induction of remission, central nervous system-directed treatment, intensification, continuation), and at 2 years post-treatment. Differences between protocols in mean HRQL scores for each phase were assessed using a t-test for independent groups. Quality-adjusted life years (QALYs), based on mean HRQL scores for and duration of each protocol phase, were used to determine the importance of differences. RESULTS: A total of 381 (00-001) and 375 (95-001) patients were assessed. There were no differences between protocols in the distribution of patients by gender (p=0.66) or risk group (p=0.56). During the first phase of treatment, the mean HRQL score of 00-01 patients (0.75) was importantly better (diff=0.18, p=0.03) than 95-001 patients (0.67).  Differences during this phase were in the attributes of dexterity (p=0.03) and emotion (p=0.009). There were no significant differences (p≥0.05) between groups during any of the other phases or post-treatment.  Over the 5 year period, 00-001 patients experienced 0.06 greater QALYs, or 3 quality-adjusted life weeks (QALW), than 95-001 patients. CONCLUSIONS: Assuming similar or reduced relapse and mortality rates, 3 QALW represents an important gain in HRQL for the more recent DFCI 00-01 protocol.