| Summary: | <b>Introduction</b>: Pre-diabetes is an intermediate, asymptomatic state between normoglycaemia and the onset of type 2 diabetes mellitus (T2D). Recent reports indicate that there are sub-clinical changes observed in red blood cells during pre-diabetes. This systematic review protocol will provide an outline of all procedures in the synthesis of the available data on the changes in red blood cell indices. <b>Methods and Analysis:</b> This protocol was prepared by adhering to the PRISMA 2015 guidelines for reporting protocols. Published clinical studies that involve observation, whether it is cross-sectional, comparative cross-sectional, case-control or cohort study designs that involve normal/non-diabetic and pre-diabetes reports were used. Additionally, this was accomplished by using clinical MeSH headings to search on MEDLINE, COCHRANE library and African Journal Online. Three reviewers (NCM, AMS & AK) screened all the results for eligibility criteria. Then, Downs and Black checklist was used to check the risk of bias. Review Manager v5.4 Forrest plot was used for meta-analysis and sensitivity analysis. Strength of evidence was then assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE). <b>Results and Conclusion:</b> This protocol will give direction on the exploration of articles that report on changes in red blood cell indices in the pre-diabetic state. The results obtained from this protocol will further give direction on the research to be done at in the eThekwini district of South Africa. <b>Ethics and Dissemination:</b> The data that will be analyzed will be data that has already been published thus there will be no data collection from subjects. Therefore, no ethical clearance is required. <b>Registration Details</b>: This protocol has been registered with the International Prospective Registry of Systematic Reviews (PROSPERO) registration number “<b>CRD42020189080</b>” dated 05-07-2020.
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