BACKGROUND. The angiotensin receptor-neprilysin inhibitor (ARNi) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i) have improved the outcome of patients with heart failure and reduced ejection fraction (HFrEF). However, data characterizing their effectiveness after cardiac resynchronization therapy (CRT) implant are relatively scarce. This study investigated the impact of ARNi and SGLT2i treatment 1) on CRT response at 12 months 2) on the cardiac function and the clinical functional status (NYHA class) at mid- and long-term follow-up 3) on the cardiac and overall survival at long-term follow-up. METHODS AND RESULTS. HFrEF patients referred for CRT implant were enrolled in the study and were grouped by the ARNi/SGLT2i therapy. The first analysis investigated the synergistic impact of these drugs started at implant on 1-year CRT response and included all 172 patients enrolled. In order to evaluate whether the time of ARNi/SGLT2i initiation after CRT response assessment is meaningful, the second analysis considered 100 patients with a follow-up > 24 months. The median follow-up was 63.1 (confidence interval [CI] 95%, 52.7 - 73.8) months. At 1-year follow-up, 40 of 51 (78.4%) patients in ARNi or SGLT2i group and 66 of 121 (54.5%) in the no treatment group were classified as responders (p = 0.006). In multivariable analysis, ARNi/SGLT2i use was an independent predictor of CRT response (odds ratio, 5.38; CI 95%, 2-16.2; p = 0.001). At mid-term follow-up (median time [interquartile range, IQR] 40.6 [25.2; 58.3] months), 61 patients started to assume these drugs. NYHA functional class improved in 23 (37.7%) patients and decreased in only 2 (3.3%) in ARNi/SGLT2i patients vs 13 (33.3%) in no treatment group (p < 0.001). ARNi and SGLT2i improved significantly also the ? LVEF, with a median [IQR] increase of 4 [2; 8] % compared to the no treatment group -1.8 [-4; 0.2] % (p < 0.001) and were independently associated with a NYHA functional class II or I at long-term (hazard ratio [HR], 3.67; CI 95%, 1.37-10.2; p < 0.001). Their estimated effectiveness was consistent over the entire follow-up period (Schoenfeld residuals test, p = 0.10), although without reaching statistical significance effects on cardiovascular survival (HR, 0.61; CI 95%, 0.25-1.50; p = 0.22). CONCLUSIONS. The ARNi and SGLT2i treatment in CRT patients improves the clinical and echocardiographic response at 12-month and long-term follow-up, independently from the time of initiation. These drugs also confer benefit on survival, however further studies are needed to confirm these data.