Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.BNP and NT-proBNP were measured before and after 4 to 6weeks, 8 to 10weeks, and 9months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.Median BNP concentration (before treatment: 202ng/l Q1 to Q3: 126 to 335ng/l) increased to 235ng/l (Q1to Q3: 128 to 422ng/l) after 8 to 10weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan causedarightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained theirprognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with nodifference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10weeks of sacubitril/valsartanwere associated with worse outcomes (p=0.003 and p=0.005, respectively).Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure PARADIGM-HF; NCT01035255).