The accurate early diagnosis of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Cystatin C might improve the early detection of AKI.207 patients presenting to the emergency department with AHF were enrolled. Cystatin C was measured in plasma in a blinded fashion at presentation and serially thereafter. The potential of Cystatin C levels to predict AKI was assessed as the primary endpoint. Long-term mortality was assessed as a secondary endpoint.At presentation, creatinine (140μmol/L [91–203] vs. 97μmol/L [76–132], p<0.01) and Cystatin C (2.00mg/L [1.30–3.08] vs. 1.45mg/L [1.00–1.90], p<0.01) levels were significantly higher in AKI compared to Non-AKI patients. The diagnostic accuracy for AKI quantified by the area under the receiver operating characteristic curve was mediocre and comparable for both markers (creatinine 0.68; 95%CI 0.58–78 vs. Cystatin C 0.67; 95%CI 0.58–0.76). Serial measurements of Cystatin C did not further increase the prognostic accuracy for AKI. Cystatin C levels were significantly higher in decedents than in survivors (1.90mg/L [1.30–2.70] vs. 1.30mg/L [1.0–1.6], p<0.001). The combination of Cystatin C and BNP levels significantly improved the prediction of mortality provided by either parameter alone. In multivariable regression analysis Cystatin C remained independently associated with mortality (HR 1.41; 95%CI 1.02–1.95).Plasma Cystatin C levels do not adequately predict AKI in patients with AHF. However, in multivariable regression analysis Cystatin C predicted mortality after the adjustment for baseline renal function, AKI, BNP levels and heart failure risk factors.