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No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events. ALCHEMIST was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, event-driven trial conducted at 64 university hospitals, general hospitals, and non-profit or private practice dialysis centres in France, Belgium, and Monaco. Adult patients aged 18 years and older with kidney failure on chronic haemodialysis with at least one cardiovascular comorbidity or risk factor were enrolled into a 4-week run-in period on open-label oral spironolactone 25 mg every other day. Participants were randomly assigned (1:1) to oral spironolactone titrated to 25 mg per day or placebo. The randomisation sequence was computer generated and stratified by centre in blocks of 4 or 6, and permutation of treatments within each block. The random assignment was double-blinded. The primary endpoint was time to first major adverse cardiovascular event (cardiovascular death, non-fatal myocardial infarction, acute coronary syndrome, stroke, or hospitalisation for heart failure) and was analysed in the intention-to-treat population. We also performed an updated meta-analysis of double-blind, randomised controlled trials of mineralocorticoid receptor antagonists in patients on haemodialysis incorporating data from ALCHEMIST. The study was registered with ClinicalTrials.gov, NCT01848639. Between June 13, 2013, and Nov 24, 2020, 1442 patients were locally screened for eligibility. 823 patients were included in the trial and 794 entered the run-in period. 644 patients were randomly assigned to spironolactone (n=320) or placebo (n=324). 444 (69%) patients were men and 200 (31%) were women. The trial was stopped prematurely due to lack of funding from the sponsor. Median follow-up was 32·6 months (IQR 17·3–48·4). The primary endpoint occurred in 78 (24%) of 320 patients in the spironolactone group (10·66 per 100 patient-years [95% CI 8·54–13·31]) and 79 (24%) of 324 patients in the placebo group (10·70 per 100 patient-years [8·59–13·35]; hazard ratio [HR] 1·00 [95% CI 0·73–1·36]; p=0·98). Hyperkalaemia above 6 mmol/L was reported in 135 (42%) patients in the spironolactone group and 134 (41%) in the placebo group (HR 1·12 [95% CI 0·88–1·43]). In the meta-analysis, mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality or non-fatal cardiovascular events and did not increase the odds of hyperkalaemia events (serum potassium concentration >6 mmol/L). In patients with kidney failure on haemodialysis and with high risk of adverse cardiovascular outcomes, spironolactone did not reduce the incidence of major cardiovascular events. The updated meta-analysis shows that mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality. Therefore, off-label use of spironolactone in this setting is not supported by available evidence. French Ministry of Health.