Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a potent predictor of death and heart failure (HF) across multiple populations. We evaluated the prognostic importance of NT-proBNP in patients with acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors enrolled in the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction). Methods: Patients were randomized to sacubitril/valsartan 200 mg or ramipril 5 mg twice daily within 0.5 to 7 days of a MI. Patients with prior HF were excluded. NT-proBNP and hs-cTnT (high-sensitivity troponin T) were collected at randomization in a prespecified substudy of 1129 patients. The primary end point of PARADISE-MI was a composite of cardiovascular death or incident HF (hospitalization or outpatient symptomatic HF), analyzed as time-to-first event; additional end points included all-cause death and the composite of fatal or nonfatal MI or stroke. Results: Median NT-proBNP was 1757 ng/L (25th–75th percentiles, 896–3462 ng/L) at randomization (4.0±1.8 days after the index MI). Patients in the highest quartile of NT-proBNP were older, more commonly women and had more hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion on presentation (all P <0.001). NT-proBNP was strongly associated with the primary end point (adjusted hazard ratio, 1.45 per doubling of NT-proBNP; [95% CI, 1.23–1.70]), adjusted for clinical variables and baseline hs-cTnT. NT-proBNP was also independently associated with all-cause death (adjusted hazard ratio, 1.74 [95% CI, 1.38–2.21]) and fatal or nonfatal MI or stroke (adjusted hazard ratio, 1.24 [95% CI, 1.05–1.45]). NT-proBNP did not significantly modify the neutral treatment effect of sacubitril/valsartan relative to ramipril ( P interaction=0.46). Conclusions: Within the first week of a high-risk MI NT-proBNP is associated with incident HF, death and atherosclerotic events. This prognostic information is independent of hs-cTnT. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02924727.