Background: In adult congenital heart disease (ACHD) patients with systemic right ventricle (RV), failure of the morphological RV cannot be avoided. The goal of our study was to examine the feasibility, efficacy, and safety of sacubitril/valsartan (SV) therapy in symptomatic ACHD patients with a failing systemic morphological RV in a biventricular circulation (BVC). Patients and methods: Sacubitril/valsartan was initiated in all symptomatic patients with failed systemic RV in a BVC after 3-month treatment with heart failure (HF) management. All patients with symptomatic hypotension, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m², or serum potassium level >5.4 mmol/L were omitted from the study. Patients' medical records including functional status, six-minute walk test (6-MWT), laboratory investigations, and echocardiography were reviewed and analyzed pre and post treatment (six months) of sacubitril/valsartan. Results: A total of 22 patients with a mean age of 38.9±8.1 years were included. Fourteen (63.6%) patients had congenitally corrected transposition of the great arteries (ccTGA) and 8 (36.4%) patients had Mustard/Senning procedure for dextro-transposition of the great arteries (d-TGA). After six-month, New York Heart Association functional-class (NYHA-FC) and 6-MWT were significantly improved (P<0.001*). The study displayed significant reductions of the brain natriuretic peptide (BNP) and the N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels (P<0.001*), without change in the potassium level or the renal function (P>0.05). The echocardiographic (ECHO) systemic RV function was significantly improved; ejection fraction (EF), tricuspid annulus plane systolic excursion (TAPSE), fractional area change (FAC), and global longitudinal strain (GLS) (P<0.05*). Conclusions: Sacubitril/valsartan is a feasible, safe, and efficient treatment in symptomatic ACHD patients with a failing systemic morphological RV in a BVC.