Introduction: Vancomycin remains one of our essential antibiotics after fifty years of treating serious infections such as methicillin-resistant Staphylococcus aureus. Vancomycin, unlike many other antibiotic agents, requires individualized dosing and monitoring of serum drug levels to ensure it is efficacious, to minimize toxicity, and to limit the development of antibiotic resistance. These issues have led to numerous vancomycin clinical practice guidelines being published in recent years including several key national guidelines. Significant resources are invested during the development of such guidelines; however, there is often little or no information about how such guidelines or other vancomycin practice improvement initiatives should be implemented. The aim of this systematic review is to identify and evaluate the effect of interventions using education, guideline implementation, and dissemination of educational resources that have sought to improve therapeutic drug monitoring and dosing of vancomycin. Methods: A systematic review of the literature will be conducted for RCTs and observational studies where a vancomycin guideline or practice improvement initiative has been implemented. Electronic databases to be searched are PubMed, Medline, CINAHL, EMBASE and the Cochrane Library of Systematic Reviews. The population will be patients who have had intravenous vancomycin prescribed and monitored in hospital. The interventions will be education, implementation of guidelines or protocols, dissemination of educational materials (printed or electronic) or multifaceted interventions of the above. The comparator will be patients who have had standard-care prescribing and monitoring of vancomycin. Outcomes will be changes in prescribing and ordering of vancomycin serum tests, and serum levels attained in patients as well as reported nephrotoxicity. Two reviewers will be involved in the quality assessment and extraction of data. The Scottish Intercollegiate Guidelines Network checklist for RCTs will be used. Studies that are not randomized will be assessed for quality using the validated ROBINS-I (risk of bias in non-randomized studies of interventions) tool. Discussion: This systematic review will identify interventions that have been used to implement guidelines and clinical practice initiatives for vancomycin. The findings of this review may be informative to those involved with the implementation of vancomycin clinical practice guidelines. Systematic review registration: PROSPERO: CRD42016049147.