Objectives: Sacubitril-valsartan reduced the risk of cardiovascular (CV) mortality among patients with heart failure with reduced ejection fraction (HFrEF). However, it is still unclear a long term protective effect on cardiac function in HFrEF patients with acute kidney injury (AKI). This study aimed to investigate the association between long term effects of CV protection and AKI treated by sacubitril-valsartan Methods: Data were retrieved from the Severance Open Big Data Portal (2016-2021). A total of 295 patients with HFrEF treated by sacubitril-valsartan or valsartan were enrolled. The participants were divided into each group to study the effect of sacubitril-valsartan in patients taking valsartan as a control group. The ratio (△ Ejection Fraction(EF)/△ estimated glomerular filtration rate(eGFR)) was used to analyze the association between CV and renal outcomes during the study period Results: The total of 295 patients with HFrEF and the rate of patient with AKI accounted for 9.5% of the total. Baseline characteristics showed that the mean age of the HFrEF patients with AKI was 76.1 ± 9.4 years, and 65.5% were male. The mean level of EF (%) were 28.0 ± 6.4 in sacubitril-valsartan group and 37.5 ± 12.6 in valsartan group (P =0.047). When the association between renal outcome and cardiovascular outcome was analyzed by independent two sample t-test, the sacubitril-valsartan group improved cardiovascular outcomes compared to valsartan group (Difference value 11.2 ± 13.1% in sacubitril-valsartan group and -0.6 ± 11.1% in valsartan group, P= 0.007). Conclusions: The present study demonstrated that HFrEF patients treated with sacubitril-valsartan had a significant improved cardiovascular outcomes even if AKI.