Background: Sepsis is a major cause of morbidity and mortality in pediatric oncology patients, particularly during periods of neutropenia, which is a well-recognized complication of immunosuppressive therapy. The current international standard of care is recognized as rapid assessment and delivery of empiric antibiotics within one hour of onset of fever for all febrile and potentially neutropenic patients. Although pediatric oncology services are centralized to tertiary hospitals in Australia, peripheral referral centres regularly provide essential supportive care for this immunosuppressed group of patients close to home in a “shared-care” model. The objective of this study was to ensure delivery of empiric antibiotics to all children with fever and suspected neutropenia within one hour of presentation to tertiary and peripheral hospitals. Methods: The records of all oncology patients presenting to an emergency department over a 3-month period were reviewed and time to first antibiotic administration recorded. Potential causes of delay in commencement of antibiotics were identified through focus groups and a questionnaires involving patients, medical and nursing staff. These were evaluated to develop an algorithmic management guideline using current available consensus data, and the introduction of the practice change was supported by staff education. Follow-up data was collected at 12 and 60 months post intervention at the tertiary and peripheral hospitals. Results: The median time to empiric antibiotics was reduced from 180 minutes to 75 minutes at 12 months post intervention, and the results were sustained at 5 years, with the median time being 65 minutes. Conclusions: The introduction of the guideline has resulted in an improvement in practice, meeting international standards and sustained results at 5 years at both tertiary and peripheral hospitals.