High-dose methotrexate (MTX) given in four hospitalizations during interim maintenance for high-risk pediatric B-lineage acute lymphocytic leukemia significantly improves survival but increases resource utilization. Children remain hospitalized for intravenous hydration and blood or urine monitoring until MTX clearance parameters are reached. Improved supportive care, extended infusion center hours, and pediatric home health expertise afford alternatives to prolonged hospital admissions, potentially offering quality, cost-effective approaches that positively impact the delivery of care.