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Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes.We measured plasma ET-1 at baseline, 48–72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9–10] pg/mL at baseline, 6.3 (IQR 4.9–8.1) pg/mL at 48–72 h, and 5.9 (IQR 4.7–7.9) pg/mL at 30 days (P < 0.001). Baseline and 48–72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3–2.0, P < 0.001 and HR 1.5, 95% CI 1.2–1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48–72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03–2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis.We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP.