Background: Cancer medication-related infusion reactions (CMIRs) can lead to treatment delays, switching to less optimal therapy, or discontinuation. Variation in the prevention, management and reporting of CMIRs was identified as a quality and safety gap by Ontario clinicians. This initiative aimed to facilitate a standardized approach to CMIRs in Ontario through the development of user-friendly health-care provider and patient resources. Methods: A multidisciplinary working group of 15 oncology clinicians (oncologists, pharmacists, nurses, administrators) with experience in the management of CMIRs reviewed available literature on CMIR assessment, prevention and management. Recommendations were based on best available evidence and group consensus when only low-level evidence was available. Final guideline content was reviewed and validated by external experts. Complementary patient information was created based on best practices in health literacy and input from patient education experts, patients and caregivers. A mechanism for system-wide reporting to track CMIRs was explored. Results: A CMIR clinical practice guideline was created. Definitions, risk factors, prophylaxis strategies, an acute management algorithm and desensitization protocols are described. A CMIR severity grading system was proposed. A toolkit was developed and contains a table outlining risk factors, mechanism, incidence, symptoms, onset, prophylaxis, acute management and re-challenge by specific drug and a tool for calculating a three-bag 12-step desensitization. Patient-friendly information was also created. A new data element for collection of CMIR incidence and severity was added to the provincial Activity Level Reporting (ALR) data set to track CMIR trends. Conclusions: A review of current evidence and expertise from oncology clinicians resulted in an evidence-informed, consensus-based guideline. This guideline and the accompanying resources can help to facilitate safe and standardized prevention and management of CMIRs across Ontario. The collection of system-wide CMIR data based on the proposed grading system will inform future quality and safety improvement initiatives.