OBJECTIVES: To assess the overall health-related quality of life (HRQL) of children diagnosed with ALL across major phases of therapy and identify areas for remediation. METHODS: All children registered in the trial at participating centres (n=5) and 5+ years of age at assessment were eligible. HRQL assessments were collected from parents using Health Utilities Index Mark 3 (HUI3) during 4 standard phases of therapy: induction (4 weeks); CNS prophylaxis (3); intensification (30); continuation (71). Differences in mean HRQL utilities were tested using ANOVA for demographic (age and gender) and clinical factors: risk status; phase; and randomization group.  Statistical significance was p<0.05 with multiple-testing adjustments. Quality-adjusted life years (QALYs) were calculated by phases for patients and general population controls. Frequency distributions identified attributes affected. RESULTS: 600 assessments were collected. Overall completion rate was 77%. Mean utilities differed (p<0.001) among phases: 0.67 induction; 0.75 CNS; 0.79 intensification; 0.87 continuation. There were no differences in mean utilities for demographic or clinical factors. QALY estimates were, for patients and controls: 0.05 and 0.07 induction; 0.04 and 0.05 CNS; 0.46 and 0.54 intensification; 1.19 and 1.27 continuation. Most of the total QALY difference was from intensification (42%) and continuation (42%). Pain was the HUI3 attribute most frequently affected among patients: 52% during intensification and 37% during continuation. Combinations of HUI3 disabilities were common. During intensification, 65% of patients with moderate/severe emotional disability also had moderate/severe pain. During continuation, 67% of patients with moderate/severe ambulation disability also had moderate/severe pain. CONCLUSIONS: The vast majority of QALYs lost by patients was associated with two phases of treatment and one health attribute. Future research to improve HRQL during treatment for ALL should focus on reducing pain during intensification and continuation phases.