Background: Hypotension remains a major clinical scenario limiting the use of novel a ngiotensin receptor-neprilysin inhibitors (ARNi) treatment for heart failure with reduced ejection fraction (HFrEF).Hypothesis: To explore the mid- to long-term cardiovascular and renal outcomes of ARNi treatment in HFrEF patients from a large-scale real-world setting.Methods: In a multi-center survey, we categorized totally 7,772 HFrEF patients (≥20 years, baseline renal replacement excluded) according to blood pressure (hypotensive status as systolic blood pressure <100mmHg) and ARNi use: Group1: Hypotensive/Non-ARNi users (n=488), Group 2: Hypotensive/ARNi users (n=311), Group 3: Normotensive/Non-ARNi users (n=4,700), and Group 4: Normotensive/ARNi users (n=2,273).Results: Hypotensive/Non-ARNi (Group 1) had smallest body mass and less likely to have baseline co-morbidity albeit higher prior myocardial infarction compared to other groups. Group 2 had slight yet significantly lower initiation dose of ARNi versus Group 4 (103.5±64.0 vs. 129.1±65.8 mg/daily, p<0.001). During a median 1.82-year follow-up, both Group 2/Group 4 HFrEF patients had significantly lower all-cause mortality and cardiovascular (CV) death, and a composite of HF hospitalization/CV death in a fully adjusted model, with Group 3 had lower all-cause and CV death (Group 1 as reference) (Table 1). There were fewer though non-significant adjusted incident new onset renal replacement therapy (HD) for Group 2, 3 and 4 compared to Group 1. Kaplan-Meier survival curves showed significant survival differences among 4 groups for all cardiovascular/mortality endpoints (all log-rank p: <0.001; worst in Group 1 vs. best survival in Group 4) except new onset HD (log-rank p: 0.29).Conclusion: Our current large-scale demonstrated that HFrEF patients with hypotension may still benefit from ARNi treatment. Hypotensive HFrEF patients should not be routinely excluded from ARNi use in a real-world setting.