<i>Objectives:</i> Recent heart failure studies have suggested that inflammatory and immune system activation are associated with increased levels of cytokines, chemokines and inflammatory proteins during acutely decompensated heart failure. The objectives of this substudy were to evaluate the role of neurohormonal and inflammatory activation in the pathogenesis and outcome of acute heart failure (AHF) and the correlation between biomarker levels and clinical outcomes. <i>Methods:</i> Serum levels of B-type natriuretic peptide-32 (BNP-32), endothelin-1 (ET-1), norepinephrine, troponins I and T, C-reactive protein (CRP), von Willebrand factor, plasminogen activator inhibitor-1, interleukin-6 (IL-6) and tissue plasminogen activator (TPA) were measured at baseline, 24 and 48 h and 7 and 30 days in 112 patients with AHF recruited to the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study neurohormonal substudy. <i>Results:</i> On univariable analysis, CRP, BNP and ET-1 were predictive of worsening heart failure by day 30; when considered together, only CRP and BNP were significantly associated with this outcome. On adjustment for age, baseline blood pressure, serum sodium and serum creatinine, only age and BNP remained significant. CRP, IL-6 and TPA levels were significantly correlated with 180-day mortality on univariable analysis. <i>Conclusion:</i> Circulating markers of inflammation may be useful in gauging prognosis in patients with AHF.