Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67±11 years; LVEF 31±6%; NT-proBNP 1822±1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318±36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p<0.05): peak VO2 and O2 pulse increased (from 15.8±3.4 to 17.0±4.0 ml/Kg/min and from 11.5±2.5 to 12.6±2.4 ml/beat, respectively), while VEVCO2 slope decreased from 35.2±11.2 to 33.1±12.3. A significant relationship (p<0.05) was observed between the amount of increase in LVEF and that of O2 pulse in all patients, and between the amount of decrease in PAPs and that of VEVCO2 slope in patients showing pulmonary hypertension in baseline. In a subgroup of 22 patients who already completed A 1 year follow-up, overall CPET improvement was maintained. In conclusion, already in the short term ARNI favorably affect cardiopulmonary response to exercise in heart failure patients; such a change seems to be preserved on a longer period.