Sacubitril/valsartan is superior to enalapril in reducing the risks of cardiovascular death and preventing hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). However, patients often do not receive sacubitril/valsartan because of concerns about hypotension. We examined the feasibility of initiating sacubitril/valsartan at a very low dose (VLD) in potentially intolerant patients with HFrEF and subsequent dose up-titration, treatment persistence and outcomes. We analyzed 206 patients with HFrEF grouped according to starting sacubitril/valsartan dose. The VLD group (n = 106) commenced 25 mg twice daily, and the standard-dose (SD) group (n = 100) started on ≥ 50 mg twice daily. Baseline systolic blood pressure was 103 ± 12 mmHg vs. 119 ± 14 mmHg in the SD group (P < 0.001). The maximal target dose achievement rate was higher in the SD group (27.0% vs 9.4%, p = 0.001) and the VLD group experienced more dose up-titrations and fewer down-titrations than the SD group. The VLD group had a decrease in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) similar to the SD group and a similar increase in left ventricular ejection fraction. There were no significant differences in symptomatic hypotension, worsening renal function, hyperkalemia, cardiovascular mortality, and rehospitalization due to HF between the two groups during follow-up period. In patients considered by the treating physician likely to be intolerant of sacubitril/valsartan, initiation with 25 mg twice daily was generally possible and patients remained in therapy, with similar decreases in NT-proBNP and increases in left ventricular ejection fraction to those observed in patients receiving SD sacubitril/valsartan.