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Background Acute decompensated heart failure (ADHF) requiring hospitalization is associated with high postdischarge mortality and readmission rates. Purpose To examine the association between achieving predischarge natriuretic peptide (NP) thresholds and mortality and readmission rates in adults hospitalized for ADHF. Data sources Multiple databases from 1947 to October 2016 (English-language studies only). Study selection Trials and observational studies that compared mortality and readmission outcomes between patients with ADHF achieving a specific predischarge NP goal and those not achieving the goal. Data extraction Two investigators independently extracted study characteristics and assessed study risk of bias. One author graded the overall strength of evidence, with review by a second author. Data synthesis One randomized trial, 3 quasi-experimental studies, and 40 observational studies were identified. The most commonly used thresholds were a brain-type NP (BNP) level of 250 pg/mL or less or an amino-terminal pro-brain-type NP (NT-proBNP) decrease of at least 30%. Achievement of absolute BNP thresholds reduced postdischarge all-cause mortality (7 of 8 studies) and the composite outcome of mortality and readmission (12 of 14 studies). Achievement of percentage-change BNP thresholds reduced the composite outcome (5 of 6 studies), and achievement of percentage-change NT-proBNP thresholds reduced all-cause and cardiovascular mortality (2 of 4 studies) and the composite outcome (9 of 9 studies). All findings were low-strength. The randomized trial, assessed as having high risk of bias, suggested that a predischarge decrease in NT-proBNP level was associated with lower risk for the composite outcome. Two quasi-experimental studies and 5 observational studies had low risk of bias. Low-risk-of-bias studies had outcome estimates similar in magnitude and direction to estimates from high-risk-of-bias studies. Limitation Most studies failed to adjust for critical confounders and had inadequate definition or assessment of exposures and outcomes. Conclusion Low-strength evidence suggests an association between achieving NP predischarge thresholds and reduced ADHF mortality and readmission. Primary funding source None.