BACKGROUND: The combination therapy of angiotensin-converting enzyme inhibitors (ACEi) or alternatively angiotensin receptor-neprilysin inhibitors (ARNis), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and recently sodium-glucose co-transporter 2 inhibitors (SGLT2is) has been hailed as a breakthrough in heart failure treatment for patients with structurally normal hearts, with international guidelines recommending these as first-line therapies ("fantastic four"). However, specific recommendations for adult with congenital heart disease (ACHD) and systemic right ventricle (sRV), who are at heightened risk for heart failure, are largely based on clinical experience or position statements, lacking robust clinical trial data. This study aims to evaluate the effectiveness and tolerability of these medications in ACHD patients with sRV. METHODS: This retrospective single-center cohort study included 21 adult patients with sRV and signs of heart failure [6 with d-transposition of the great arteries (d-TGA) post-atrial switch, 7 with congenitally corrected transposition of the great arteries (cc-TGA), and 8 with univentricular right heart in Fontan circulation]. Changes in functional New York Heart Association (NYHA) class, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, sRV function, and renal function were assessed before and after initiating or escalating heart failure pharmacotherapy with ARNi and/or SGLT2i. The median follow-up was 15 months (1.24 years). RESULTS: The combination therapy was well tolerated among all patients, with no interruptions in therapy and no adverse effects such as hyperkalemia, renal dysfunction, or significant hypotension reported. Among the 21 patients with follow-up data, 12 were treated with the full combination of guideline-directed therapy, including ARNi and SGLT2i. NYHA class improved in 62.0% of patients (P=0.002), and the median NT-proBNP level decreased from 870 (range, 593-1,774) to 373 (range, 189-743) ng/L (P=0.002). However, no significant change in ventricular function was detected by echocardiography. CONCLUSIONS: Our preliminary findings suggest that in ACHD patients with a sRV the new guideline-directed heart failure pharmacotherapy regimen is well tolerated and leads to improvements in NYHA class and reductions in NT-proBNP levels. Further randomized studies are needed to confirm these promising results and to explore the effects of SGLT2i, either alone or in combination, in this patient population.