Blood cystatin C has increasingly been used as an endogenous marker for estimating glomerular filtration rate (GFR) and evaluating prognosis in patients with acute or chronic heart failure. The goal of the study was to investigate the impact of heart failure on the determination of renal function based on cystatin C or creatinine in nonacute cardiac patients. A total of 880 consecutive and clinically stable patients with heart disease were prospectively evaluated. Serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) showed a stronger correlation with cystatin C (r = 0.60, p <0.001) compared with creatinine (r = 0.46, p <0.001). Multivariate analysis identified estimated GFR according to the MDRD Study formula (p <0.001), serum NT-pro-BNP (p <0.001), use of immunosuppressive agents (p <0.001), and allopurinol treatment (p <0.001) as the strongest independent predictors of serum cystatin C. Parallel measurement of creatinine clearance using timed urine collection in a subgroup of 160 patients showed that estimated GFR according to cystatin C was almost identical to measured creatinine clearance independent of NT-proBNP. Conversely, creatinine-based calculation using the MDRD Study formula underestimated GFR in patients from the low (12 to 238 pg/ml) and medium (241 to 990 pg/ml) NT-pro-BNP tertiles. In conclusion, in patients without severe heart failure, indicated by low serum NT-pro-BNP, estimation of GFR using creatinine-based formulas underestimated renal function. The known prognostic impact of cystatin C in cardiac patients might result from a strong correlation with NT-pro-BNP, as well as its superior ability to predict renal function in patients with and without heart failure.