Objectives The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). Background β-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. Methods A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. Results Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l range 0.80 to 1.49 mg/l vs. 0.88 mg/l range 0.68 to 1.17 mg/l, p = 0.003) and cystatin C (1.29 mg/l range 1.00 to 1.71 mg/l vs. 1.03 mg/l range 0.86 to 1.43 mg/l, p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m2 , elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. Conclusions Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication.