BACKGROUND: Acute kidney injury (AKI) is common and often leads to significant morbidity and/or death. The development of AKI, or complications associated with it, may be due to use of certain medications in at-risk patients experiencing an intercurrent illness. Implicated drugs include diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), metformin and sulfonylureas. Expert consensus opinion (and clinical guidelines) recommend considering discontinuation of diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs, metformin and sulfonylureas in the event of an intercurrent illness to prevent AKI onset or reduce severity or complications. However, the evidence base for these recommendations is very limited. This systematic review aims to address the available evidence for the temporary discontinuation of diuretics, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, non-steroidal anti-inflammatories and metformin and sulfonylureas for those at risk of AKI or with newly diagnosed AKI. METHODS/DESIGN: Randomised controlled trials; non-randomised trials; cohort studies; case-control studies; interrupted time series studies; and before-and-after studies featuring adults aged 18 and over in any setting currently taking diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs and metformin; experiencing an intercurrent illness; or undergoing a radiological/surgical procedure (planned or unplanned) will be searched for. Relevant trial registers and systematic review databases will be searched. Systematic reviews will be assessed for methodological quality using the ROBIS tool, trials will be assessed using the Cochrane risk of bias tool, and observational studies will be assessed using the ACROBAT-NRS tool. If sufficient studies assessing similar populations, study type, settings and outcomes are found, then a formal meta-analysis will be performed to estimate summary measures of effect. If not, a narrative synthesis will be adopted. DISCUSSION: This review will synthesise evidence for the efficacy of discontinuing diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs, metformin or sulfonylureas to prevent or delay onset of AKI or associated complications. Results will provide guidance on efficacy and safety of this strategy and potentially help to develop an intervention to test the best mechanism of guiding medication discontinuation in at-risk populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023210.