Cardiac rehabilitation (CR) and Valsartan/Sacubitril (VS) association improved morbi-mortality and quality of live in patients (P) with Heart Failure and reduced Ejection Fraction (HFrEF), but few studies reported their impact on global systolic function and physical capacities. We evaluated the benefits of CR and VS in HFrEF P under optimal therapy (OT) (betablocker+conversion enzyme inhibitor or Angiotensin 2 receptor antagonist+Aldosterone antagonist+diuretics+Electric Resynchronization [ER] if necessary) on echocardiographic left ventricular (LV) EF and cardiorespiratory testing (CRT). VS was associated when OT was obtained (initial dosage 24/26mg or 49/51 if tolerated). During follow-up, one P died, two were excluded for renal failure and nine were lost, leaving 26/38 P for final analysis (25 male, 62.5±12 yo, 25±7kg/m2). 14 and 12 presented with ischemic (IC) and dilated (DC) cardiomyopathy. Peak oxygen uptake (VO2) and oxygen uptake at the first ventilatory threshold (VT1) were evaluated from CRT on a bicycle ergometer. All variables were serially measured at inclusion (T0), end of CR (28±9 sessions,T1), as well six (T2) and twelve (T3) months later. LVEF in HFrEF P improved gradually from T0 to T2 (T0: 32.1±7 vs. T1: 40.1±8%, p=0.006; vs. T2: 46.7±9%, P<0.0001; T1vsT2, p=0.03) and then plateaued (T3: 49.6±10%, T2vsT3, NS). Interestingly, LVEF kinetics differed between IC and DC P, values increasing up to T1 only in IC while constantly improving up to T3 in DC. Peak VO2 also gradually increased up to T2, differences with baseline being however significant only after six months (T0: 15.3±5.3 vs. T1: 18.4±6.6ml/min/kg, NS; vs. T2: 20.7±6.3ml/min/kg, p=0.01) before levelling-off (T3: 20.9±5.8ml/min/kg, T2vsT3 NS). Similar results were obtained for VT1 (Table 1, Fig. 1). CR associated to VS in P presented with HFrEF is able to enhance global systolic function and cardiorespiratory fitness parameters, improvement being particularly significant in the DC population.