Objective To observe the efficacy and safety of very low-dose titration of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction (HFrEF) combined with low systolic blood pressure. Methods A total of 86 patients with HFrEF with low systolic blood pressure hospitalized in the Department of Cardiology of Binzhou Medical University Hospital from January 2019 to June 2021 were retrospectively selected as the study subjects. There were 43 cases in the control group and the observation group, and the control group was given sacubitril/valsartan from 25mg twice a day, and the dose was doubled once every 2~4 weeks until the maximum tolerated dose was reached; The observation group was given sacubitril/valsartan from a small dose of 25 mg once a day, and the dose was doubled every 4~8 weeks until the maximum tolerated dose was reached. After 12 months of treatment, the changes of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and left ventricular short axis shortening rate (LVFS), N-terminal B-type natriuretic peptide (NT-proBNP), soluble growth-stimulating expression of gene 2 protein (sST2), blood potassium, serum creatinine and blood pressure were recorded before and after treatment, and the medication status and safety of the two groups were compared. Results NT-proBNP, sST2, and LVDd were reduced in both groups, while LVEF and LVFS were elevated, and these improvements were more significant in the observation group (P＜0.001), the dose of sacubitril-valsartan in the observation group was higher than that in the control group (P＜0.001), the difference in serum potassium and serum creatinine between the two groups was not significant (P＞0.05), the systolic blood pressure in the control group after treatment was lower than that in the observation group (P＜ 0.001), the difference in diastolic blood pressure was not statistically significant (P＞0.05), and the incidence of symptomatic hypotension and rehospitalization was lower in the observation group (P＜0.001 and P＜0.05, respectively). Conclusion The treatment of HFrEF combined with low systolic blood pressure, with very small dose of slow titration of sacubitril/valsartan, can significantly improve the cardiac function and have a high safety profile