Abstract Background: Current guidelines approved Sacubitril/ valsartan as replacement therapy to angiotensin-converting-enzyme inhibitors or angiotensin-receptor-blockers for treat-ment of heart failure patients with reduced ejection fraction. Aim of Study: The study was conducted to evaluate the safety, efficacy, and tolerability of sacubitril/valsartan (S/V) initiation in hospitalized patients. Patients and Methods: This is a Prospective observational cohort study that included 191 patients who were hospitalized due to heart failure with reduced Ejection fraction (HFrEF) from March 2019 till June 2020. Sacubitril/valsartan was initiated during hospitalization and after hemodynamic stabi-lization. The study evaluated the following: Incidence of hypotensive events, the incidence of inpatient acute kidney injury and hyperkalemia, rate of discontinuation, and change in ejection fraction (EF), Brain natriuretic peptide (BNP), and N-terminal Pro-B-type natriuretic peptide (NT-pro-BNP) from baseline and after one and three months from initiation. Results: The mean age was 60.4±12.4 years and 73.8% of patients were males. Of the studied group, 92.1 % continued to take S/V, while 3.1% stopped medicine due to symptomatic hypotension, 2.6% due to financial issues, 1% due to AKI, and 1% due to hyperkalemia. After three months, only 5.8% of the patients tolerated the maximum dose (97-103) bid. For patients who continued to take S/V, there was a significant increase in EF at one- and three-month post-initiation, 28.4% vs. 33.8% & 28.4% vs. 39.4% respectively, (p < 0.001). On the other hand, there was a significant decrease in both BNP and NT-pro-BNP, (p < 0.001). Conclusions: Early initiation of sacubitril/valsartan during hospitalization is safe and tolerable with good efficacy and minimal adverse effects. Key Messages: Most hospitalized patients due to acute decompensated heart failure and reduced ejection fraction can tolerate initiation of sacubitril/valsartan after hemodynamic stabilization guided by strict blood pressure, creatinine, and potassium level monitoring.