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Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002–2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1–1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5–1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5–1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase–treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. C17 Research Network. • Few studies compare health care use or cost of different paediatric acute lymphoblastic leukaemia protocols. • We compared population-based patient cohorts treated with Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI) protocols. • We found more emergency department visits with COG but more outpatient visits with DFCI. • During the study period, cost intensity was higher among DFCI patients. • Strategies minimising burden of both protocols are warranted. [ABSTRACT FROM AUTHOR]