OBJECTIVES: Renin–angiotensin–aldosterone system inhibitors (RAASi) are well characterised treatments for renal protection in patients with chronic kidney disease (CKD). However, the increased risk of hyperkalaemia often results in RAASi discontinuation. A systematic review (SR) was conducted to assess whether: i) RAASi affects CKD progression, ii) there are long-term clinical benefits of RAASi in patients with CKD, and iii) discontinuation/down-titration of RAASi affects patients’ long-term health. METHODS: Randomised controlled trials (RCTs) published between 1998 and January 2019 were identified by interrogating Medline, Embase, and Cochrane databases. Eligible RCTs included adults with CKD or diabetic nephropathy treated with RAASi. Studies recruiting patients on dialysis were excluded. Outcomes included long-term measures of clinical benefit (cardiovascular [CV] events, hospitalisation, mortality) and disease progression (changes in glomerular filtration rate [GFR], time to end stage renal disease [ESRD]). RESULTS: Of the 12,761 publications screened, 7 RCTs reported the clinical benefits of RAASi and 27 RCTs measured disease progression following treatment. RAASi significantly delayed the development of ESRD in 3/5 RCTs, and significantly reduced the risk of ‘doubling of serum creatine or need for renal replacement therapy’ (composite endpoint) in 2/3 studies versus placebo. A significant reduction in the rate GFR decline was observed in 3/8 RCTs versus placebo. RAASi significantly (or numerically) reduced ‘all-cause mortality’, ‘CV-mortality’ and ‘CV-events’ versus placebo in 1/2 RCTs, 2/4 RCTs and 5/7 RCTs, respectively. No RCTs examined long-term outcomes following withdrawal/down-titration of RAASi; however, one RCT suggested that low versus high dose of RAASi significantly increased the risk of the composite endpoint ‘doubling of serum creatine, ESRD, or death’. CONCLUSIONS: Results indicate that RAASi treatment delays the progression to ESRD and reduces the risk of some CV outcomes in patients with CKD. Further evidence would continue to develop our understanding on the long-term outcomes of discontinuing/down-titrating RAASi therapies.