IntroductionRenin-angiotensin system (RAS) plays a key role in various types of cardiovascular disease and many kinds of RAS inhibitors have been developed. The effect of discontinuation of RAS inhibitors on clinical outcomes is still controversial. This study aims to evaluate the effects of discontinuing RAS inhibitor medication on the clinical outcomes of patients continuously taking these agents.Methods and analysisThis article presents a systematic review protocol described in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. We will include randomised controlled trials in which the effects of RAS inhibitor withdrawal were evaluated. Initially, four authors will search for eligible studies in MEDLINE, EMBASE, the Cochrane Database Trial Register, European trial registry and ClinicalTrials.gov. Abstracts and full-text screenings will be performed by the four authors with data extraction performed by each author independently. We will include patients taking RAS inhibitors—including ACE inhibitor, angiotensin receptor blocker and angiotensin receptor neprilysin inhibitor and exclude the patients undergoing renal replacement therapy (RRT), adolescents (under 18 years of age) and patients with acute infectious diseases. Our search will be performed on 1 May 2023. Studies in which the patients discontinued RAS inhibitors due to any reason will be included. Patients who continuously took RAS inhibitors under conditions in which the intervention group discontinued these agents will be considered eligible as the comparison group. Death (any cause), Death (cardiovascular disease (CVD)) and CVD events will be set as primary outcomes. Secondary outcomes will be set as RRT, acute kidney injury, renal function (analysis of the change in estimated glomerular filtration rate), hyperkalaemia, proteinuria and blood pressure.Ethics and disseminationResearch ethics approval was not required in this study due to it being a systematic review, and any data belonging to individuals cannot be identified. The results of this study will be disseminated through peer-reviewed journals and conferences.Trial registration numberPROSPERO CRD42022300777.