Background End-stage renal disease (ESRD) patients even without known cardiovascular (CV) disease have high mortality rates. Whether neurohormonal blockade treatments improve outcomes in this population remains unknown. The aim of this study was to assess the effect of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), β-blockers or both in all-cause mortality rates in incident ESRD patients without known CV disease starting renal replacement therapy (RRT) between 2009 and 2015 in the nationwide Réseau Epidémiologie et Information en Néphrologie registry. Methods Patients with known CV disease and those who started emergency RRT, stopped RRT or died within 6 months were excluded. Propensity score matching models were used. The main outcome was all-cause mortality. Results A total of 13 741 patients were included in this analysis. The median follow-up time was 24 months. When compared with matched controls without antihypertensive treatment, treatment with ACEi/ARBs, β-blockers and ACEi/ARBs + β-blockers was associated with an event-rate reduction per 100 person-years: ACEi/ARBs 7.6 [95% confidence interval (CI) 7.1–8.2] versus matched controls 9.5 (8.8–10.1) [HR 0.76 (95% CI 0.69–0.84)], β-blocker 7.1 (6.6–7.7) versus matched controls 9.5 (8.5–10.2) [HR 0.72 (0.65–0.80)] and ACEi/ARBs + β-blockers 5.8 (5.4–6.4) versus matched controls 7.8 (7.2–8.4) [HR 0.68 (0.61–0.77)]. Conclusions Neurohormonal blocking therapies were associated with death rate reduction in incident ESRD without CV disease. Whether these relationships are causal will require randomized controlled trials.