Background: In PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-pro BNP in Patients Stabilized From an Acute Heart Failure Episode), the in-hospital initiation of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure (ADHF) was well-tolerated and led to improved outcomes. We aim to determine the representativeness of the PIONEER-HF trial among patients hospitalized for ADHF using real-world data. Methods: The study population was derived from all patients discharged alive for ADHF in the Get With The Guidelines—HF registry from 2006 to 2018 with HF with reduced ejection fraction (HFrEF; all HFrEF with ADHF). We then determined the proportion of patients meeting PIONEER-HF eligibility criteria (PIONEER-HF eligible) and those meeting a set of limited eligibility criteria (actionable cohort). Rates of HF readmissions and all-cause mortality were then compared between the all HFrEF with ADHF, PIONEER-HF eligible, and actionable cohorts using linked Medicare claims data. Results: A total of 99 767 patients with HFrEF in Get With The Guidelines—HF were hospitalized for ADHF. PIONEER-HF inclusion criteria were met by 71 633 (71.8%) patients, and both inclusion and exclusion criteria were met by 20 704 (20.8%) patients. Further, 68 739 (68.9%) patients met the criteria for the actionable cohort. Among the Centers for Medicare and Medicaid—linked patients, the HF rehospitalization rate at 1 year was 35.1% (95% CI, 34.5–35.8) for all HFrEF with ADHF patients, 32.6% (95% CI, 31.3–33.9) for the PIONEER-HF eligible cohort, and 33.1% (95% CI, 32.3–33.9) for the actionable cohort. The 1-year all-cause mortality was 36.7% (95% CI, 36.1–7.4) for all HFrEF with ADHF patients, 31.6% (95% CI, 30.3–32.9) for the PIONEER-HF eligible cohort, and 32.2% (95% CI, 31.4–33.0) for the actionable cohort. Conclusions: Patient characteristics and clinical outcomes for patients eligible for PIONEER-HF only modestly differ when compared with those encountered in routine practice, suggesting that the in-hospital initiation of sacubitril/valsartan should be routinely considered for patients with HFrEF hospitalized for ADHF.