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Background: The effect of sacubitril/valsartan on survival and hospitalization risk in older patients with heart failure has not been explored. We aimed to investigate the risk of hospitalization and mortality with the use of sacubitril/valsartan vs. enalapril in patients with heart failure. Methods: This was a population-based cohort study using the Hong Kong-wide electronic healthcare database. Patients diagnosed with heart failure and newly prescribed sacubitril/valsartan or enalapril between July 2016 and June 2019 were included. The risk of primary composite outcome of cardiovascular mortality or heart failure-related hospitalization, all-cause hospitalization, heart failure-related hospitalization, cardiovascular mortality and all-cause mortality were compared using Cox regression with inverse probability treatment weighting. Additional analysis was conducted by age stratification. Results: Of the 44,503 patients who received sacubitril/valsartan or enalapril, 3,237 new users (sacubitril/valsartan, n = 1,056; enalapril, n = 2,181) with a diagnosis of heart failure were identified. Compared with enalapril, sacubitril/valsartan users were associated with a lower risk of primary composite outcome [hazard ratio (HR) 0.58; 95% confidence interval (CI), 0.45-0.75], heart failure-related hospitalization (HR 0.59; 95% CI, 0.45-0.77), all-cause mortality (HR 0.51; 95% CI, 0.36-0.74) and borderline non-significant reductions in all-cause hospitalization (HR 0.85; 95% CI, 0.70-1.04) and cardiovascular mortality (HR 0.63; 95% CI, 0.39-1.02). The treatment effect of sacubitril/valsartan remains unaltered in the patient subgroup age ≥ 65 years (73%). Conclusions: In real-world settings, sacubitril/valsartan was associated with improved survival and reduced heart failure-related hospitalization compared to enalapril in Asian patients with heart failure. The effectiveness remains consistent in the older population., Competing Interests: EWC has received research funding from Bayer, Bristol-Myers Squibb, Pfizer, and Takeda, for work unrelated to this study. ICKW has received research funding outside the submitted work from Amgen, Bayer, Bristol-Myers Squibb, GSK, and Janssen. XL has received a research grant from Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pathadka, Yan, Li, Tse, Wan, Lau, Lau, Siu, Chan and Wong.)